CN111683688A - 听力损失的基因疗法治疗 - Google Patents

Abstract

本发明涉及病毒载体、特别是腺相关病毒(AAV)载体，并涉及其在听力损失、特别是基于Otoferlin基因(OTOF)的一种或多种突变的听力损失的基因疗法治疗中的用途。

Description

听力损失的基因疗法治疗

技术领域

本发明涉及病毒载体、特别是腺相关病毒(AAV)载体，并涉及其在听力损失、特别是基于Otoferlin基因(OTOF)的一种或多种突变的听力损失的基因疗法治疗中的用途。

背景技术

听觉是一个复杂的过程，通过耳朵和大脑感知和处理声音信号。听力损失是听力障碍，甚至是耳聋/失聪。根据WHO分级，听力损失可分为轻度(最弱可感知声音在25-40dB之间；WHO 1)、中(度)(最弱可感知声音在41-60dB之间；WHO 2)、重度/高度(最弱可感知声音在61-80dB之间；WHO 3)、以及非常严重或接近耳聋(最弱可感知声音在81dB以上；WHO 4)。原因是多方面的，包括例如过度噪声暴露(最常见的原因)、年龄、各种疾病和遗传原因。遗传性听力损失的发生率约为1/650-1000，目前已知其中的缺陷/突变与听力损失有关的基因有100多种。根据WHO分级，全球约有3.6亿人、在德国18岁以上的人群中约有16％是重听。在65岁以上中，这意味着两个男人中就有一个，三个女人中有一个。

涉及Otoferlin基因(OTOF，所述基因编码多C2域蛋白Otoferlin)的突变导致严重的、非综合征形式的语前DFNB9听力损失或温度敏感的听突触病(参见，例如Yasunaga等，Nat.Genet.1999，21:363-369；Varga等，J.Med.Genet.2006，43:576-581；Shearer和Smith

Seattle(WA)，华盛顿大学，西雅图，1993-2018；Santarelli等，HearRes.2015，330：200-212；

等，Trends Neurosci.2012，35(11):671-680；Rodríguez-Ballesteros等，Hum Mutat 2008，29:823-831)。从临床角度来看，在一些西方人群中，OTOF介导的失聪占所有自身隐性非综合征性耳聋病例的5-8％(Rodríguez-Ballesteros等，Hum Mutat 2008，29:823-831)，使其成为目前仍无治疗方案的五大遗传性听力障碍之一(Angeli等，Anat Rec(Hoboken)2012，295:1812-1829)。

关于Otoferlin的分子功能，目前众所周知的是Otoferlin在耳蜗的感觉内毛细胞(IHC)中表达，并在耳蜗内毛细胞与螺旋神经节传入神经元的突触的突触前囊泡融合的最后步骤中发挥关键作用(Roux等，Cell2006，127:277-289)。已经提出了Otoferlin的几种功能，例如在以下方面发挥作用：(i)突触前Ca²⁺结合，以引发毛细胞去极化后的囊泡胞吐(参见，例如Roux等，Hum Mol Genet 2009，18:4615-4628；Beurg等，J Neurosci 2010，30:13281-13290；Johnson等，Nat Neurosci 2010，13:45-52；Michalski等，Elife 2017，6)；以及(ii)突触囊泡在释放部位的囊泡启动和补充，以确保即使在长时间的刺激中也能不间断地及时精确释放神经递质(参见，例如

等，Nat Neurosci 2010，13:869-876；Vogl等，J Cell Sci 2015，128:638-644；Jung等，EMBO J 2015，34:2686-2702；Strenzke等，EMBO J 2016，35:2519-2535；Vogl等，EMBO J 2016，35:2536-2552)。

遗传性听力障碍(如基于Otoferlin基因(OTOF)突变的听力损失)的患者由于目前尚无药物可以恢复听力，也没有其它抗因治疗方法，因此通常只能使用助听器或人工耳蜗。基因疗法(即把缺陷基因的完整拷贝引入耳部受影响的群体中)可能代表着在单基因性(但也包括后天性)听力损失病例中恢复听力的重要一步，例如，动物研究显示，通过基因疗法，突变小鼠的听力得到部分改善(参见，例如Akil等，Neuron 2012，75:283-293；Askew等，Sci.Transl.Med.2015，7:295ra108；Jung等，EMBO J 2015，34:2686-2702；Landegger等，Nat Biotechnol 2017，35:280-284)。每种单基因性听觉疾病都需要开发单独的基因治疗(病毒)构建体，将有关的修复基因导入到受影响的细胞中，而此类构建体目前还没有广泛使用。

迄今为止，生成了数种Otof小鼠突变体(Roux等，Cell 2006，127:277-289；

等，Nat Neurosci 2010，13:869-876；Strenzke等，EMBO J 2016，35:2519-2535)以及其它小鼠模型，其中，感觉毛细胞中Otoferlin蛋白水平大幅降低(例如AP2μ，Jung等，EMBO J 2015，34:2686-2702；Wrb，Vogl等人，EMBO J 2016，35:2536-2552)，这强调了Otoferlin在毛细胞突触前的突触前释放中的生理重要性。事实上，Otof缺失突变体(Otof敲除)是完全聋的，因此代表了研究通过野生型序列的纠正性病毒处理进行遗传恢复(拯救)的有用模型系统。本发明的发明人已经建立了向出生后的小鼠内耳注射病毒的方法，这种方法可以进行后续的体内分析(即关于脑干测听[ABR]阈值和ABR振幅等)以及离体单细胞分析(突触前膜片钳电生理学、免疫组化等)，以确定和验证某些拯救构建体的治疗潜力。

由于Otoferlin编码序列的大小(>5.5kb)和标准腺相关病毒载体(由于其良好的安全性，经常用于基因治疗应用)的包装尺寸有限(AAV；<4.4kb；Grieger和Samulski JVirol 2005，79:9933-9944)，建立具有全长Otoferlin的基因疗法是一个重大挑战。

因此，本发明的目的是提供基因治疗性病毒载体以及相应的基因治疗方法，以用于治疗基于Otoferlin基因(OTOF)突变的听力损失。

发明内容

本发明提供了病毒载体，所述病毒包含核酸，所述核酸包含启动子以及与之可操作地连接的编码序列，所述编码序列编码Otoferlin或其功能片段或变体。

在实施方式中，所述病毒载体选自于由以下所组成的组：腺相关病毒载体(AAV载体)、腺病毒载体、慢病毒载体、单纯疱疹病毒(HSV)载体、痘苗病毒载体和仙台病毒载体。

在实施方式中，所述核酸为DNA或RNA，优选为DNA。

在实施方式中，所述病毒载体为AAV载体或腺病毒载体。

在实施方式中，AAV载体选自于由以下所组成的组：AAV-PHP.B、AAV-PHP.eB、AAV-PHP.S和AAV-Anc80。

在实施方式中，AAV载体选自于由以下所组成的组：AAV-8、AAV-9和AAV-1/2。

在实施方式中，启动子选自于由以下所组成的组：巨细胞病毒(CMV)启动子，人β肌动蛋白/CMV杂合启动子，鸡β肌动蛋白/CMV杂合启动子，CMV-肌动蛋白-球蛋白(CMV-Actin-Globin，CAG)杂合启动子，Math1启动子，VGLUT3启动子，小白蛋白(Parvalbumin)启动子，Calretinin启动子，Calbindin28k启动子，Prestin启动子，Otoferlin启动子，以及肌球蛋白II启动子、V启动子、VI启动子、VIIa启动子或XVa启动子。

在实施方式中，启动子为人β肌动蛋白/CMV杂合启动子。

在实施方式中，所述编码序列编码全长Otoferlin。

在实施方式中，所述病毒载体为外泌体(Exosomen)相关的病毒载体。

在实施方式中，病毒载体为exo-AAV载体

在另一方面，本发明提供了药物组合物，所述药物组合物包含本发明的病毒载体以及药学上可接受的载体或赋形剂。

在另一方面，本发明提供了用作药物使用的本发明的病毒载体或本发明的药物组合物。

在另一方面，本发明提供了本发明的病毒载体或本发明的药物组合物用于治疗听力损失的方法。

在实施方式中，听力损失为基于Otoferlin基因(OTOF)的一种或多种突变的听力损失。

在实施方式中，听力损失为DFNB9听力损失。

在实施方式中，所述方法包括将病毒载体给予至内耳、特别是耳蜗、特别是耳蜗的内毛细胞。

在实施方式中，给予包括：通过圆窗注射；经由镫骨切开术(Stapedotomie)注射到前庭阶(Scala vestibuli)；经由耳蜗切开术(Cochleostomie)注射到鼓阶；和/或以储积物(Depot)形式应用到圆窗龛中(例如作为凝胶、海绵的组成部分)，或者通过应用导管应用到圆窗龛中。

在实施方式中，给予使得耳蜗内毛细胞中Otoferlin或其功能片段或变体表达。

在另一方面，本发明提供了本发明的病毒载体在制备治疗听力损失的药物中的用途。

在实施方式中，听力损失是基于Otoferlin基因(OTOF)的一种或多种突变的听力损失。

在实施方式中，听力损失为DFNB9听力损失。

在另一方面，本发明提供了治疗听力损失的方法，所述方法包括将本发明的病毒载体给予至内耳、特别是耳蜗、特别是耳蜗的内毛细胞。

在实施方式中，听力损失是基于Otoferlin基因(OTOF)的一种或多种突变的听力损失。

在实施方式中，听力损失为DFNB9听力损失。

在实施方式中，给予包括：通过圆窗注射；经由镫骨切开术注射到前庭阶；经由耳蜗切开术注射到鼓阶；和/或以储积物形式应用到圆窗龛中(例如作为凝胶、海绵的组成部分)，或者通过应用导管应用到圆窗龛中。

在实施方式中，给予使得耳蜗内毛细胞中Otoferlin或其功能片段或变体表达。

附图说明

图1示出了全长Otoferlin的克隆策略的示意图(A)和具有全长Otoferlin的顺式质粒的载体图(B)。

图2示出了用于在HEK293T细胞中生产病毒颗粒的质粒pHelper(Takara/Clontech；A)和tTA-iCAP-PHPb(Trans-Plasmid；B)的载体图，其提供了病毒衣壳PHP.B(Deverman等，Nat.Biotechnol.2016，34:204-209)。

图3示出了病毒介导的Otoferlin敲除小鼠的听力恢复，其中，A为用于AAV-PHP.B载体的Otoferlin拯救构建体的示意图(C₂A-F–C₂A-F结构域；CC-卷曲螺旋结构域；FerB-Ferlin B结构域；TM-跨膜结构域)；B为AAV-PHP.B载体构建体的示意图，其携带处于人β肌动蛋白/CMV杂合启动子的控制下的Otoferlin cDNA；B’和B”示出了出生后(p5-7)将病毒注射到小鼠耳蜗的方法；C示出了OTOF-KO小鼠的内毛细胞中AAV-PHP.B介导的Otoferlin外源性表达(Calretinin作为复染色，用于内毛细胞的特异性标记，比例尺5μm)；以及，D、D’和D”示出了在成年后对出生后注射OTOF-KO小鼠的脑干测听(听性脑干反应，AuditoryBrainstem Recording，ABR)，表明通过AAV-PHP.B-Otoferlin载体成功恢复ABR振幅和平均短声阈值(Klick-Schwellenwerten)(**p<0.005)。

具体实施方式

本发明提供了病毒载体，所述病毒载体包含核酸，所述核酸包含启动子以及与之可操作地连接的编码序列，所述编码序列编码Otoferlin或其功能片段或变体。

在实施方式中，核酸为DNA或RNA，优选为DNA。核酸在本文中也可称为基因构建体。

术语“病毒载体”是指用于将遗传物质(例如编码Otoferlin或其功能片段或变体的编码序列)导入靶细胞的病毒颗粒。这种遗传物质的运输称为“转导”。

在实施方式中，病毒载体选自于由以下所组成的组：腺相关病毒载体(AAV载体)、腺病毒载体、慢病毒载体、单纯疱疹病毒(HSV)载体、痘苗病毒载体和仙台病毒载体。合适的病毒载体例如在Sacheli等的“基因疗法”2012，1-11中有所描述。

在实施方式中，病毒载体为AAV载体或腺病毒载体(例如Ad5、Ad28或Hd-Ad)。

在优选的实施方式中，病毒载体是AAV载体。

术语“AVV载体”包括所有血清型的AAV载体以及基于不同血清型的组合的AAV载体(也称为“杂合型AAV载体”或“假型AAV载体”)。在实施方式中，AAV载体为选自于由以下所组成的组中的血清型的AAV载体：AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-11、AAV-7m8，及它们的组合。合成的AAV变体AAV-7m8例如在Dalkara等Sci Transl Med 2013，5(189):189ra76中描述。还包括其它合成的AAV载体，例如AAV-PHP.B、AAV-PHP.B2、AAV-PHP.B3、AAV-PHP.A、AAV-PHP.eB和AAV-PHP.S(Deverman等，NatureBiotechnol 2016，34:204-209；Chan等，Nature Neuroscience 2017，20:1172-1179)或者AAV-Anc80(WO 2017/100791A1；Landegger等，Nat Biotechnol 2017，35:280-284；Zinn等，Cell Rep.2015，12(6):1056-1068)。合适的AAV载体也可商购获得，例如来自Penn VectorCore(PA，USA)和SignaGen Laboratories(MD，USA)。

在实施方式中，AAV载体为AAV-8载体或AAV-9载体。

在实施方式中，AAV载体为AAV-1/2载体。术语“AAV-1/2载体”是指其基因组以镶嵌形式封装在血清型1和血清型2的衣壳中的AAV载体(参见，例如Choi等，Curr GeneTher.2005，5(3):299-310)。在优选的实施方式中，其为血清型2(AAV-2)的基因组。

在实施方式中，AAV载体是合成的AAV载体。在优选的实施方式中，AAV载体选自于由以下所组成的组：AAV-PHP.B、AAV-PHP.eB、AAV-PHP.S和AAV-Anc80。在实施方式中，AAV载体是AAV-7m8载体或者AAV-7m8与另一血清型的组合。

在实施方式中，病毒载体为单病毒载体。在实施方式中，病毒载体不是双病毒载体，例如不是双AAV载体。

在实施方式中，病毒载体是外泌体相关的病毒载体，优选exo-AAV载体。用于生产外泌体相关的病毒载体的方法是本领域技术人员已知的，例如包括通过超离心从生产细胞的条件培养基中分离外泌体相关的病毒载体(参见例如Hudry等，Gene Ther.2016 23(4):380-392)。例如，外泌体相关的病毒载体的特征在于对病毒感染后体内产生的中和抗AAV抗体的抵抗力增强，这有助于提高转导效率。

在实施方式中，启动子是组成型启动子。本文所用的术语“组成型启动子”是指允许其相关基因持续表达的非调控型启动子。

在实施方式中，启动子选自于由以下所组成的组：巨细胞病毒(CMV)启动子，人β肌动蛋白/CMV杂合启动子，鸡β肌动蛋白/CMV杂合启动子，CMV-肌动蛋白-球蛋白(CAG)杂合启动子，Math1启动子，VGLUT3启动子，小白蛋白启动子，Calretinin启动子，Calbindin28k启动子，Prestin启动子，Otoferlin启动子，以及肌球蛋白II启动子、V启动子、VI启动子、VIIa启动子或XVa启动子。

在实施方式中，启动子为人β肌动蛋白/CMV杂合启动子。

在实施方式中，Otoferlin为野生型Otoferlin。在实施方式中，Otoferlin为人Otoferlin(参见例如UniProt-Datenbank ID：Q9HC10)。在实施方案中，人Otoferlin包含选自于由SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:7和SEQ ID NO:9所组成的组中的氨基酸序列，或者由选自于由SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:7和SEQ ID NO:9所组成的组中的氨基酸序列组成。在实施方式中，人Otoferlin包含氨基酸序列SEQ ID NO:1或SEQ ID NO:3，或者由氨基酸序列SEQ ID NO:1或SEQ ID NO:3组成。在优选的实施方式中，人Otoferlin包含氨基酸序列SEQ ID NO:1，或者由所述氨基酸序列组成。

术语“功能片段”是指具有与Otoferlin相同或基本上相同(例如+/-20％或+/-10％)的功能活性的Otoferlin片段。在实施方式中，所述功能片段为Otoferlin的N端和/或C端截短形式。在实施方式中，所述功能片段包含Otoferlin的至少500个、600个、700个、800个、900个、1000个、1100个、1200个、1300个、1400个、1500个、1600个、1700个、1800个或1900个连续氨基酸残基。Otoferlin的功能片段优选为具有足够长的氨基酸序列的片段以确认该片段为Otoferlin的片段，并排除非Otoferlin的蛋白质的片段。

在实施方式中，所述变体为Otoferlin的功能变体，例如具有与Otoferlin相同或基本上相同(例如+/-20％或+/-10％)的功能活性的Otoferlin的变体。

在实施方式中，所述变体包含一个或多个氨基酸插入、氨基酸添加、氨基酸删除和/或氨基酸置换。在实施方案中，所述变体包含至多30个、25个、20个、19个、18个、17个、16个、15个、14个、13个、12个、11个、10个、9个、8个、7个、6个、5个、4个、3个或2个氨基酸的插入、添加、删除和/或置换(例如保守置换)。

本文所用的术语“变体”也可指Otoferlin的天然存在的突变体、变体和同源物(例如直系同源物(Orthologe))。在实施方式中，天然存在的同源物是小鼠Otoferlin。在实施方式中，小鼠Otoferlin包含选自于由SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15和SEQID NO:17所组成的组中的氨基酸序列，或者由选自于由SEQ ID NO:11、SEQ ID NO:13、SEQID NO:15和SEQ ID NO:17所组成的组中的氨基酸序列组成。在优选的实施方式中，小鼠Otoferlin包含氨基酸序列SEQ ID NO:11，或者由氨基酸序列SEQ ID NO:11组成。

在实施方式中，所述变体包含与选自于由以下所组成的组中的氨基酸序列具有至少70％、至少75％、至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％同一性的氨基酸序列；或者由与选自于由以下所组成的组中的氨基酸序列具有至少70％、至少75％、至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％同一性的氨基酸序列组成：SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15和SEQ ID NO:17，优选SEQ ID NO:1或SEQ ID NO:3，更优选SEQ ID NO:1。

在实施方式中，上述Otoferlin的功能活性是全部或部分地恢复Otof敲除小鼠的内毛细胞的突触前神经递质释放的能力，例如通过电生理上测量的去极化相关的膜容量的增加(相当于突触信使囊泡与突触前质膜的融合，即“胞吐”；Roux等，Cell 2006，127:277-289；Vogl等，EMBO J 2016，35:2536-2552)。在实施方式中，上述Otoferlin的功能活性是指恢复Otof敲除小鼠内毛细胞中Otoferlin表达的能力，例如可用免疫组化单细胞或组织RNA测序或者单细胞或组织PCR分析在胞浆或毛细胞浆膜中进行检测。在实施方式中，上述Otoferlin的功能活性是恢复Otof敲除小鼠的全部或部分听力的能力，如通过脑干测听(听性脑干反应，ABR)测定，例如基本上如实施例2所述。

在实施方式中，所述编码序列包含与选自于由以下所组成的组中的核苷酸序列具有至少70％、至少75％、至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％同一性的核苷酸序列，或者由与选自于由以下所组成的组中的核苷酸序列具有至少70％、至少75％、至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％同一性的核苷酸序列组成：SEQ ID NO:2、SEQ ID NO:4、SEQ IDNO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16和SEQ IDNO:18，优选SEQ ID NO:2或SEQ ID NO:4，更优选SEQ ID NO:2。在实施方式中，所述编码序列包含核苷酸序列SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16和SEQ ID NO:18，优选SEQ ID NO:2或SEQ IDNO:4，更优选SEQ ID NO:2；或者所述编码序列由核苷酸序列SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16和SEQ ID NO:18，优选SEQ ID NO:2或SEQ ID NO:4，更优选SEQ ID NO:2组成。

两个核苷酸序列或氨基酸序列的相似性(例如由其同一性的百分比表示)可通过序列比对来确定。此类比对可用本领域技术人员已知的不同算法进行，优选使用Karlin和Altschul的数学算法(Karlin&Altschul Proc.Natl.Acad.Sci.U.S.A.1993，90:5873-5877)，例如使用hmmalign(HMMER Package，http://hmmer.wustl.edu/)，或使用CLUSTAL算法(Thompson J.D.等，Nucleic Acids Res.1994，22:4673-80)，例如其可从http://www.ebi.ac.uk/Tools/clustalw/或http://www.ebi.ac.uk/Tools/clustalw2/index.html或http://npsa-pbil.ibcp.fr/cgi-bin/npsa_automat.pl？page＝/NPSA/npsa_clustalw.html获得。

在本发明的病毒载体的优选实施方式中，所述编码序列编码全长Otoferlin(full-length Otoferlin)。

在实施方式中，根据本发明的病毒载体(例如AAV载体)中包含的核酸含有进一步的序列元件。此类序列元件包括例如反向末端重复(ITR；例如AAV-2ITR)、Kozak序列、抗性基因(例如AmpR)、多聚腺苷酸化序列(例如牛生长激素bGH的多聚腺苷酸化序列)以及调控元件(例如土拨鼠肝炎病毒转录后调控元件(WPRE))。此外，所述核酸还可以包含其它编码序列。此类其它编码序列例如可以编码额外的治疗活性肽/蛋白或者标记蛋白(例如荧光蛋白，如EGFP)。在实施方式中，根据本发明的病毒载体(例如AAV载体)中所包含的核酸包含ITR、启动子以及与之可操作地连接的编码Otoferlin或其功能片段或变体的编码序列、WPRE序列和多聚腺苷酸化序列(参见例如图3B)。

在另一方面，本发明提供了如本文所述的核酸(或基因构建体)。

在另一方面，本发明提供了包含本发明的病毒载体或本发明的核酸(或基因构建体)的宿主细胞。该宿主细胞可为原核细胞(例如细菌细胞)或真核细胞(例如真菌细胞、植物细胞或动物细胞)。优选地，所述宿主细胞是分离的。在实施方式中，所述宿主细胞为生产细胞或生产细胞系，所述生产细胞或生产细胞系能够例如基于本发明的核酸(或基因构建体)并通过共转染合适的辅助构建体(例如辅助质粒)来生产根据本发明的病毒载体(例如AAV载体)(参见例如US 2004/0235174A1)。合适的生产细胞或生产细胞系是本领域技术人员已知的，包括例如HEK293细胞或HEK293T细胞。

在另一方面，本发明提供了含有本发明的病毒载体或本发明的核酸(或基因构建体)的非人转基因动物。术语“非人转基因动物”特别是指非人灵长类动物或其它动物，特别是哺乳动物，如牛、马、猪、绵羊、山羊、狗、猫、猴(Affe)、原猴类；鸟类，如鸡；或啮齿动物，如小鼠、大鼠、豚鼠、仓鼠和蒙古沙鼠。

生产病毒载体的方法是本领域技术人员已知的。生产例如AAV载体的方法包括三重转染合适的生产细胞系(例如HEK293或HEK293T)，随后通过碘克沙醇或氯化铯梯度进行纯化。用三种载体转染生产细胞：在第一载体/质粒上，编码感兴趣的基因(此处：Otoferlin)，两侧是相应的包装信号(参见图1B)；在第二载体/质粒上，编码所需的AAV蛋白，特别是Rep和Cap(例如tTA-iCAP-PHPb；参见图2B)；以及，第三载体/质粒提供腺病毒辅助功能，没有这些功能，AAV颗粒的生产是不可能的(例如pHelper，Takara/Clontech；参见图2A)。合适的方法也在Grieger等(Nature Protocols 2006，1(3):1412-1428)中进行了描述。

在另一方面，本发明提供了药物组合物，所述药物组合物包含本发明的病毒载体和药学上可接受的载体或赋形剂。

根据本发明的药物组合物优选为无菌的，并且含有治疗有效量的病毒载体。

“治疗有效量”是指单独或与其它剂量结合使用时产生预期反应或效果的量，例如听力的改善或者部分或完全恢复。治疗有效量将取决于待治疗的病症；疾病的严重程度；患者的个体状况，包括年龄、生理状况、身高和体重；治疗持续时间；同步疗法的类型(如果有的话)；具体给药途径和类似因素。

在实施方式中，给予约10⁸至约10¹³个病毒颗粒，所述病毒颗粒悬浮在适当体积的载体中。

可能的载体(例如溶剂)为例如人工外淋巴液(künstliche Perilymphe)、无菌水、林格氏溶液、乳酸林格氏溶液、生理盐水溶液、抑菌盐溶液(例如含0.9％苯甲醇的盐溶液)、磷酸盐缓冲盐溶液(PBS)、Hanks溶液、固定油、聚亚烷基二醇、氢化萘和生物相容性的聚乳酸、丙交酯/乙交酯共聚物或聚氧乙烯/聚氧丙烯共聚物。所得的溶液或悬浮液优选为等渗的。合适的载体及其配方也在Remington’s Pharmaceutical Sciences，1985年第17版，Mack Publishing Co.中有详细描述。

在优选的实施方式中，载体为人工外淋巴液。

本文使用的术语“赋形剂”包括可能包含在药物组合物中而本身并非活性成分的所有物质，例如盐类、粘结剂(如乳糖、葡萄糖、蔗糖、海藻糖、山梨醇、甘露醇)、润滑剂、增稠剂、表面活性剂、防腐剂、乳化剂、缓冲剂、稳定剂、调味剂或着色剂。

术语“药学上可接受的”是指优选不与药物组合物的活性成分的作用相互作用的无毒物质。特别是，术语“药学上可接受的”是指所讨论的物质已被政府管理当局批准用于动物特别是人，或者已在美国药典、欧洲药典或其它公认的药典被列出用于动物特别是人。

在另一方面，本发明提供了作为药物使用的本发明的病毒载体或本发明的药物组合物。

本文所用的术语“药物”是指治疗上使用(即用于治疗、改善或预防疾病或健康疾患)的物质或组合物。

在另一方面，本发明提供了本发明的病毒载体或本发明的药物组合物用于治疗听力损失的方法。

根据本发明，待治疗的患者或个体是人、非人灵长类动物或其它动物，特别是哺乳动物，如牛、马、猪、绵羊、山羊、狗、猫、猴、原猴类；鸟类，如鸡；或者啮齿动物，如小鼠、大鼠、豚鼠、仓鼠和蒙古沙鼠。在特别优选的实施方式中，待治疗的患者或个体是人。

在实施方式中，听力损失是基于Otoferlin基因(OTOF)的一种或多种突变的听力损失。

在实施方式中，治疗的患者或个体在Otoferlin基因中具有一种或多种突变，特别是抑制或阻断Otoferlin的表达和/或功能的突变。

在实施方式中，听力损失是DFNB9听力损失。

在实施方式中，所述方法包括将病毒载体给予至内耳、特别是耳蜗、特别是耳蜗的内毛细胞。

在实施方式中，给予包括：通过圆窗注射；经由镫骨切开术注射到前庭阶；经由耳蜗切开术注射到鼓阶；和/或以储积物形式应用到圆窗龛中(例如作为凝胶、海绵的组成部分)，或者通过应用导管应用到圆窗龛中。

在实施方式中，给予包括鼓室(intratympanale)注射。

在实施方式中，所述给予使得Otoferlin或其功能片段或变体在耳蜗的内毛细胞中表达，例如在耳蜗顶端螺旋的内毛细胞中表达。

根据本发明，术语“表达”以其最一般的含义使用，并包括例如RNA的产生或RNA和蛋白的产生。

在实施方式中，本发明的病毒载体、本发明的药物组合物以及本发明的方法和用途允许Otoferlin或其功能片段或变体在至少50％、至少60％、至少70％、至少80％、至少90％或至少95％的耳蜗内毛细胞中、优选耳蜗顶端螺旋的内毛细胞中表达。

根据本发明的病毒载体和根据本发明的药物组合物以治疗有效量给予。

在另一方面，本发明提供了本发明的病毒载体在制备用于治疗听力损失的药物中的用途。

在实施方式中，听力损失为基于Otoferlin基因(OTOF)的一种或多种突变的听力损失。

在实施方式中，听力损失为DFNB9听力损失。

在另一方面，本发明提供了治疗听力损失的方法，所述方法包括将本发明的病毒载体给予至内耳、特别是耳蜗、特别是耳蜗的内毛细胞。

在实施方式中，听力损失为基于Otoferlin基因(OTOF)的一种或多种突变的听力损失。

在实施方式中，听力损失为DFNB9听力损失。

在实施方式中，给予包括：通过圆窗注射；经由镫骨切开术注射到前庭阶；经由耳蜗切开术注射到鼓阶；和/或以储积物形式应用到圆窗龛中(例如作为凝胶、海绵的组成部分)，或者通过应用导管应用到圆窗龛中。

在实施方式中，给予包括鼓室注射。

在实施方式中，给予使得Otoferlin或其功能片段或变体在耳蜗的内毛细胞中表达，例如在耳蜗顶端螺旋的内毛细胞中表达。

实施例

实例1：表达全长Otoferlin的病毒载体的生成

克隆程序和策略

将来自小鼠的全长Otoferlin(full-length Otoferlin，flOtoferlin)(SEQ IDNO:11/12)从先前生产的cDNA克隆(pcDNA3-mOtof-IRES-EGFP)亚克隆到pAAV载体中。

由于Otoferlin编码核苷酸序列内缺乏合适的限制性位点，并且全长OtoferlincDNA相当长，因此避免使用传统的基于T4连接酶的克隆技术。而使用了fusion克隆策略，其中，首先用限制性酶NheI和HindIII(Fermentas)消化将目标载体(pAAV)线性化。然后，对3个Otoferlin片段进行扩增，所述片段与flOtoferlin互补，并且所述片段彼此之间以及与线性化的目标载体之间含有重叠序列。该步骤需要对片段和引物进行优化，例如通过确定最佳片段大小和比例，以及使用“拆分重叠(Split Overlaps)”来减少引物长度。NheI/HindIII线性化的pAAV目标载体，Otoferlin片段A、片段B、片段C以及所用引物的位置如图1A所示。引物A_F2包含5'端与目标载体的15bp重叠以及Otoferlin表达的起始密码子，而C_R2包含终止密码子以及3'端与AAV载体的15bp重叠(参见

表1)。

表1用于克隆的引物。引物以5'-3'方向示出，重叠序列用下划线表示，转录的起始密码子和终止密码子用粗体和斜体表示。

然后按照制造商的说明，使用In-Fusion HD克隆试剂盒(Takara/Clontech)将线性化载体和三个片段融合。该方法产生了最终的全长Otoferlin病毒载体(pAAV-flOtoferlin)，用于后续的病毒生产。带有普遍存在的人β肌动蛋白/CMV杂合启动子的pAAV-flOtoferlin的相应载体图在图1B中示出。使用限制性酶消化和Sanger测序(SeqLab，德国)验证正确的flOtoferlin插入。

病毒生产和纯化

使用聚乙烯亚胺(25,000MW，Polysciences，USA)转染在HEK293T细胞(ATCC)中生成AAV(Gray等，Current Protocols in Neuroscience2011，Hoboken NJ，USA：John Wiley&Sons,Inc.；Deverman等，Nat.Biotechnol.2016，34:204-209)。简而言之，借助pHelper质粒(Takara/Clontech，参见图2A)、提供病毒衣壳PHP.B的反式质粒(Deverman等，Nat.Biotechnol.2016，34:204-209；参见图2B)以及提供flOtoferlin的顺式质粒(参见图1B)，实现对HEK293T细胞的三重转染。定期对细胞系进行支原体检测。转染后72小时从培养基中收集病毒颗粒，转染后120小时从细胞和培养基中收集病毒颗粒。在4℃下将来自培养基中的病毒颗粒用处于500mM NaCl中的40％聚乙二醇8000(Acros Organics，德国)沉淀2小时，4000g离心30分钟后与细胞沉淀合并处理。将细胞沉淀在37℃下悬浮在500mM NaCl、40mM Tris、2.5mM MgCl₂、pH 8和100U/mL盐活化核酸酶(Arcticzymes，USA)中30分钟。然后，通过在2,000g下离心10min使细胞裂解物澄清，然后以58,400U/min通过碘克沙醇不连续梯度(Optiprep，Axis Shield，挪威；15％、25％、40％和60％)纯化2.25小时(Zolotukhin等，Gene Ther.1999，6:973-985；Nature Protocols 2006，1(3):1412-1428)。将病毒用Amicon过滤器(EMD，UFC910024)进行浓缩，并在补充有0.001％Pluronic F-68(Gibco，USA)的无菌磷酸盐缓冲盐溶液(PBS)中进行配制。根据制造商的说明，用AAV滴定试剂盒(Takara/Clontech)测定病毒滴度，用qPCR(StepOne，Applied Biosystems)测定DNase I抗性vg的数量。根据制造商的说明，在凝胶电泳(Novex^TM4-12％Tris-Glycine，Thermo FisherScientific)后，通过银染色(Pierce，德国)常规地检查所产生的病毒的纯度。在所有病毒制剂中都确认了病毒衣壳蛋白的存在。病毒母液在-80℃下保存至试验日。

实施例2：表达全长Otoferlin的病毒载体的体内应用

动物与病毒传播

通过圆窗在左耳的鼓阶(鼓阶)中实施的出生后AAV注射(约1-1.5μL的病毒制剂；1.29×10¹²GC/ml)(在p5-p7时进行)基本上如Akil等的研究中所述(Akil等，Neuron 2012，75:283-293)。使用Otoferlin敲除(Otof-/-)小鼠，其听力严重受损，对高达120dB的声压级没有显示出ABR反应(Reisinger等，J.Neurosci.2011，31:4886-4895)。注射4周后，通过脑干测听(听性脑干反应，ABR)测试听力(内毛细胞的功能)。然后在麻醉下无痛地处死动物，对所提取耳蜗进行提取，用于免疫组化分析。所有实验均按照国家动物护理指南进行，并得到哥廷根大学动物福利委员会和下萨克森州动物福利办公室的批准(AZ：33.4-42502-04-14/1391)。

脑干测听(听性脑干反应，ABR)

为了ABR分析，用氯胺酮(125mg/kg)和噻拉嗪(2.5mg/kg)的组合对小鼠进行i.p.麻醉。借助热毯(Hugo Sachs Elektronik–Harvard Apparatus GmbH)，使核心温度保持恒定在37℃。对于刺激的产生、展现和数据采集，使用TDT III系统(Tucker DavisTechnologies)，其由单独编写的Matlab软件(Mathworks)操作。用JBL 2402扬声器，将音频脉冲(4/6/8/12/16/24/32kHz，10ms平台(Plateau)，1ms cos²上升/下降(Steigung/Fall))或0.03ms短声以40Hz(音频脉冲)或20Hz(短声)在自由场展示。将头顶针和乳突针之间的电位差放大50,000倍，过滤(400-4,000Hz)，并以50kHz的频率采样20ms，进行1,300次，以获得每个声音强度的两个中间ABR图形。按照最低刺激强度，以10dB的精度来确定听力阈值，通过两个独立观察者的视觉检查在两个图形中产生可重复的反应波形。将超过最大扬声器输出(100dB SPL)的音频脉冲阈值评估为110dB。关于拯救实验，首先对Otof敲除小鼠的注射耳进行记录。然后，用电极凝胶(Pauli-Magnus等，Neuroscience 2007，149:673-684)和小纤维素织物条封闭左耳，从而实现30-40dB的传导性听力损失(Pauli-Magnus等，Neuroscience 2007，149:673-684)，并对未注射耳进行记录。

免疫组化和共聚焦显微术

如先前所述(Khimich等，Nature 2005，434:889-894；Meyer等，Nat.Neurosci.2009，12:444-453)，在冰上将耳蜗分离快固定在处于PBS的4％甲醛中(10分钟或1小时，取决于分子靶标)。在洗涤和用含山羊血清的缓冲液(16％正常山羊血清，450mMNaCl，0.3％Triton X-100和20mM磷酸盐缓冲液，pH 7.4)封闭后，在4℃下过夜施用以下一抗：小鼠抗Otoferlin(货号ab53233；Abcam)、鸡抗Calretinin(货号214 106；SynapticSystems)。为了可视化，在室温下施用AlexaFluor-488、AlexaFluor-568和AlexaFluor-647缀合的二抗(货号A-11034、A-11011、或A-11075和A-21236；Thermo Fisher Scientific)1小时。在Mowiol中固定盖玻片和载玻片之间的标本后，在Aberior Instruments ExpertLine STED显微镜(基于倒置Olympus IX83显微镜)上在共焦模式下进行图像采集，其由Imspector软件控制，使用485nm和640nm激发激光和1.4NA UPlanSApo 100×油浸物镜。以60×60nm的xy像素尺寸和200nm的Z步长获取图像栈。

结果

图3中的实验数据显示，使用编码Otoferlin的病毒载体进行基因治疗的方法确实是可行的，并且具有临床潜力。

出生后早期用全长Otoferlin转导Otoferlin敲除小鼠在耳蜗的内毛细胞(IHC)中达到了临床相关的转导率(图3C)，并使成年动物的ABR阈值显著降低(图3D-图3D")，相当于听力得到了有力的改善。AAV注射到左耳后，在注射和未注射的耳中都可以诱发ABR，而在未注射的动物中，即使在最高水平上也未能引发ABR。未注射侧ABR的引发可能是由左内耳(尽管诱发了传导性听力损失)的过度听觉

引起的。此外，没有观察到不良的副作用。

序列表

<110> 乔治-奥古斯特-哥廷根大学公法大学医学基金会

<120> 听力损失的基因疗法治疗

<130> 979-4 PCT

<150> DE 10 2018 103 924.7

<151> 2018-02-21

<160> 24

<170> PatentIn version 3.5

<210> 1

<211> 1997

<212> PRT

<213> 智人（Homo sapiens）

<400> 1

Met Ala Leu Leu Ile His Leu Lys Thr Val Ser Glu Leu Arg Gly Arg

1 5 10 15

Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser

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Arg Val Leu Glu Asn Cys Glu Asp Val Ala Asp Phe Asp Glu Thr Phe

35 40 45

Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Met Leu Glu Ile

50 55 60

Gln Val Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr

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Phe Arg Met Val Leu Gln Lys Val Val Glu Glu Ser His Val Glu Val

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Thr Asp Thr Leu Ile Asp Asp Asn Asn Ala Ile Ile Lys Thr Ser Leu

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Cys Val Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Ser Trp

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Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Glu Lys

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Asp Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Ser

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Arg Pro Pro Gly Glu Lys Ser Phe Arg Arg Ala Gly Arg Ser Val Phe

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Ser Ala Met Lys Leu Gly Lys Asn Arg Ser His Lys Glu Glu Pro Gln

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Arg Pro Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu

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Ala Ile Arg Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala

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Ser Val Thr Ala Leu Thr Thr Asn Val Ser Asn Lys Arg Ser Lys Pro

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Asp Ile Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val

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Ser Ile Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp

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Pro Val Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met

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Lys Glu Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp

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Phe His Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser

305 310 315 320

Val Ile His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser

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Phe Lys Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe

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His His Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ser Gly

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Leu Lys Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp

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Asn Ile Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile

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Glu Gly Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp

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Ala Arg Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met

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Gln Val Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys

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Val Gln Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr

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His Phe Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe

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Leu Pro Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg

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Asn Tyr Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly

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Glu Gly Val Ser Phe Arg Ala Arg Leu Leu Leu Gly Leu Ala Val Glu

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Ile Val Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln

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Val Glu Gln Ala Thr Pro Ile Ser Glu Ser Cys Ala Gly Lys Met Glu

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Glu Phe Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg

610 615 620

Arg Asn Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr

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Gly Asn Glu Val Asp Gly Leu Ser Arg Pro Gln Arg Pro Arg Pro Arg

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Lys Glu Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ala Ser

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Asp Asp Glu Ala Gly Asp Ala Gly Asp Leu Ala Ser Val Ser Ser Thr

675 680 685

Pro Pro Met Arg Pro Gln Val Thr Asp Arg Asn Tyr Phe His Leu Pro

690 695 700

Tyr Leu Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp

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Gln Arg Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp

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Lys Leu Glu Glu Gly Leu Asn Asp Ile Gln Glu Met Ile Lys Thr Glu

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Lys Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser

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Cys Gly Cys Cys Arg Phe Leu Ser Leu Ala Asp Lys Asp Gln Gly His

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Ser Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg

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Glu Leu Glu Asn Met Gly Gln Gln Ala Arg Met Leu Arg Ala Gln Val

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Lys Arg His Thr Val Arg Asp Lys Leu Arg Leu Cys Gln Asn Phe Leu

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Gln Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp

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Ile Phe Ile Trp Met Met Ser Asn Asn Lys Arg Val Ala Tyr Ala Arg

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Val Pro Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Thr Gly

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Lys Asp Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys

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Arg Gly Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Val Glu Leu

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Tyr Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys Glu Phe Leu Cys Gly

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Leu Pro Cys Gly Phe Gln Glu Val Lys Ala Ala Gln Gly Leu Gly Leu

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His Ala Phe Pro Pro Val Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe

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Gln Leu Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp

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Ser Ser Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln

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Ser Gln Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp

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Glu Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp

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Gly Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro

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Pro Asp Arg Ser Ala Pro Ser Trp Asn Thr Thr Val Arg Leu Leu

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Arg Arg Cys Arg Val Leu Cys Asn Gly Gly Ser Ser Ser His Ser

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Glu Lys Lys Lys Pro Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys

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Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser

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Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly Ser Leu Cys

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Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu Ala Gly

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Tyr Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn Asp

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Pro Ile Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp

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Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala

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Ile Arg Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile

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Ser Lys Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu

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Ala Ser Phe Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp

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Trp Asp Leu Val Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile

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Asp Leu Glu Asn Arg Phe Tyr Ser Lys His Arg Ala Thr Cys Gly

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Lys Val Asp Gly Pro His Phe Gly Pro Pro Gly Arg Val Lys Val

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Ala Asn Arg Val Phe Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn

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Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys Arg Leu Val Pro

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Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly

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Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe Pro Met

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Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys

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Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu

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Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser

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Asp Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys

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Gln Asp Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn

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Phe Asn Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu

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Glu Lys Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp

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Glu Thr Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp

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Asp Ala Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu

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Cys Thr Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val

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Ser Ile Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu

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Ala Arg Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu

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Ala Glu Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro

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Val Gly Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn

1925 1930 1935

Arg Pro Asp Thr Ala Phe Val Trp Phe Leu Asn Pro Leu Lys Ser

1940 1945 1950

Ile Lys Tyr Leu Ile Cys Thr Arg Tyr Lys Trp Leu Ile Ile Lys

1955 1960 1965

Ile Val Leu Ala Leu Leu Gly Leu Leu Met Leu Gly Leu Phe Leu

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Tyr Ser Leu Pro Gly Tyr Met Val Lys Lys Leu Leu Gly Ala

1985 1990 1995

<210> 2

<211> 5994

<212> DNA

<213> 智人（Homo sapiens）

<400> 2

atggccttgc tcatccacct caagacagtc tcggagctgc ggggcagggg cgaccggatc 60

gccaaagtga ctttccgagg gcaatccttc tactctcggg tcctggagaa ctgtgaggat 120

gtggctgact ttgatgagac atttcggtgg ccggtggcca gcagcatcga cagaaatgag 180

atgctggaga ttcaggtttt caactacagc aaagtcttca gcaacaagct catcgggacc 240

ttccgcatgg tgctgcagaa ggtggtagag gagagccatg tggaggtgac tgacacgctg 300

attgatgaca acaatgctat catcaagacc agcctgtgcg tggaggtccg gtatcaggcc 360

actgacggca cagtgggctc ctgggacgat ggggacttcc tgggagatga gtctcttcaa 420

gaggaagaga aggacagcca agagacggat ggactgctcc caggctcccg gcccagctcc 480

cggcccccag gagagaagag cttccggaga gccgggagga gcgtgttctc cgccatgaag 540

ctcggcaaaa accggtctca caaggaggag ccccaaagac cagatgaacc ggcggtgctg 600

gagatggaag accttgacca tctggccatt cggctaggag atggactgga tcccgactcg 660

gtgtctctag cctcagtcac agctctcacc actaatgtct ccaacaagcg atctaagcca 720

gacattaaga tggagccaag tgctgggcgg cccatggatt accaggtcag catcacggtg 780

atcgaggccc ggcagctggt gggcttgaac atggaccctg tggtgtgcgt ggaggtgggt 840

gacgacaaga agtacacatc catgaaggag tccactaact gcccctatta caacgagtac 900

ttcgtcttcg acttccatgt ctctccggat gtcatgtttg acaagatcat caagatttcg 960

gtgattcact ccaagaacct gctgcgcagt ggcaccctgg tgggctcctt caaaatggac 1020

gtgggaaccg tgtactcgca gccagagcac cagttccatc acaagtgggc catcctgtct 1080

gaccccgatg acatctcctc ggggctgaag ggctacgtga agtgtgacgt tgccgtggtg 1140

ggcaaagggg acaacatcaa gacgccccac aaggccaatg agaccgacga agatgacatt 1200

gaggggaact tgctgctccc cgagggggtg ccccccgaac gccagtgggc ccggttctat 1260

gtgaaaattt accgagcaga ggggctgccc cgtatgaaca caagcctcat ggccaatgta 1320

aagaaggctt tcatcggtga aaacaaggac ctcgtggacc cctacgtgca agtcttcttt 1380

gctggccaga agggcaagac ttcagtgcag aagagcagct atgagcccct gtggaatgag 1440

caggtcgtct ttacagacct cttcccccca ctctgcaaac gcatgaaggt gcagatccga 1500

gactcggaca aggtcaacga cgtggccatc ggcacccact tcattgacct gcgcaagatt 1560

tctaatgacg gagacaaagg cttcctgccc acactgggcc cagcctgggt gaacatgtac 1620

ggctccacac gtaactacac gctgctggat gagcatcagg acctgaacga gggcctgggg 1680

gagggtgtgt ccttccgggc ccggctcctg ctgggcctgg ctgtggagat cgtagacacc 1740

tccaaccctg agctcaccag ctccacagag gtgcaggtgg agcaggccac gcccatctcg 1800

gagagctgtg caggtaaaat ggaagaattc tttctctttg gagccttcct ggaggcctca 1860

atgatcgacc ggagaaacgg agacaagccc atcacctttg aggtcaccat aggcaactat 1920

gggaacgaag ttgatggcct gtcccggccc cagcggcctc ggccccggaa ggagccgggg 1980

gatgaggaag aagtagacct gattcagaac gcaagtgatg acgaggccgg tgatgccggg 2040

gacctggcct cagtctcctc cactccacca atgcggcccc aggtcaccga caggaactac 2100

ttccatctgc cctacctgga gcgaaagccc tgcatctaca tcaagagctg gtggccggac 2160

cagcgccgcc gcctctacaa tgccaacatc atggaccaca ttgccgacaa gctggaagaa 2220

ggcctgaacg acatacagga gatgatcaaa acggagaagt cctaccctga gcgtcgcctg 2280

cggggcgtcc tggaggagct gagctgtggc tgctgccgct tcctctccct cgctgacaag 2340

gaccagggcc actcatcccg caccaggctt gaccgggagc gcctcaagtc ctgcatgagg 2400

gagctggaaa acatggggca gcaggccagg atgctgcggg cccaggtgaa gcggcacacg 2460

gtgcgggaca agctgaggct gtgccagaac ttcctgcaga agctgcgctt cctggcggac 2520

gagccccagc acagcattcc cgacatcttc atctggatga tgagcaacaa caagcgtgtc 2580

gcctatgccc gtgtgccctc caaggacctg ctcttctcca tcgtggagga ggagactggc 2640

aaggactgcg ccaaggtcaa gacgctcttc cttaagctgc cagggaagcg gggcttcggc 2700

tcggcaggct ggacagtgca ggccaaggtg gagctgtacc tgtggctggg cctcagcaaa 2760

cagcgcaagg agttcctgtg cggcctgccc tgtggcttcc aggaggtcaa ggcagcccag 2820

ggcctgggcc tgcatgcctt cccacccgtc agcctggtct acaccaagaa gcaggcgttc 2880

cagctccgag cgcacatgta ccaggcccgc agcctctttg ccgccgacag cagcggactc 2940

tcagacccct ttgcccgcgt cttcttcatc aatcagagtc agtgcacaga ggtgctgaat 3000

gagaccctgt gtcccacctg ggaccagatg ctggtgttcg acaacctgga gctctatggt 3060

gaagctcatg agctgaggga cgatccgccc atcattgtca ttgaaatcta tgaccaggat 3120

tccatgggca aagctgactt catgggccgg accttcgcca aacccctggt gaagatggca 3180

gacgaggcgt actgcccacc ccgcttccca cctcagctcg agtactacca gatctaccgt 3240

ggcaacgcca cagctggaga cctgctggcg gccttcgagc tgctgcagat tggaccagca 3300

gggaaggctg acctgccccc catcaatggc ccggtggacg tggaccgagg tcccatcatg 3360

cccgtgccca tgggcatccg gcccgtgctc agcaagtacc gagtggaggt gctgttctgg 3420

ggcctacggg acctaaagcg ggtgaacctg gcccaggtgg accggccacg ggtggacatc 3480

gagtgtgcag ggaagggggt gcagtcgtcc ctgatccaca attataagaa gaaccccaac 3540

ttcaacaccc tcgtcaagtg gtttgaagtg gacctcccag agaacgagct gctgcacccg 3600

cccttgaaca tccgtgtggt ggactgccgg gccttcggtc gctacacact ggtgggctcc 3660

catgccgtca gctccctgcg acgcttcatc taccggcccc cagaccgctc ggcccccagc 3720

tggaacacca cggtcaggct tctccggcgc tgccgtgtgc tgtgcaatgg gggctcctcc 3780

tctcactcca caggggaggt tgtggtgact atggagccag aggtacccat caagaaactg 3840

gagaccatgg tgaagctgga cgcgacttct gaagctgttg tcaaggtgga tgtggctgag 3900

gaggagaagg agaagaagaa gaagaagaag ggcactgcgg aggagccaga ggaggaggag 3960

ccagacgaga gcatgctgga ctggtggtcc aagtactttg cctccattga caccatgaag 4020

gagcaacttc gacaacaaga gccctctgga attgacttgg aggagaagga ggaagtggac 4080

aataccgagg gcctgaaggg gtcaatgaag ggcaaggaga aggcaagggc tgccaaagag 4140

gagaagaaga agaaaactca gagctctggc tctggccagg ggtccgaggc ccccgagaag 4200

aagaaaccca agattgatga gcttaaggta taccccaaag agctggagtc cgagtttgat 4260

aactttgagg actggctgca cactttcaac ttgcttcggg gcaagaccgg ggatgatgag 4320

gatggctcca ccgaggagga gcgcattgtg ggacgcttca agggctccct ctgcgtgtac 4380

aaagtgccac tcccagagga cgtgtcccgg gaagccggct acgactccac ctacggcatg 4440

ttccagggca tcccgagcaa tgaccccatc aatgtgctgg tccgagtcta tgtggtccgg 4500

gccacggacc tgcaccctgc tgacatcaac ggcaaagctg acccctacat cgccatccgg 4560

ctaggcaaga ctgacatccg cgacaaggag aactacatct ccaagcagct caaccctgtc 4620

tttgggaagt cctttgacat cgaggcctcc ttccccatgg aatccatgct gacggtggct 4680

gtgtatgact gggacctggt gggcactgat gacctcattg gggaaaccaa gatcgacctg 4740

gagaaccgct tctacagcaa gcaccgcgcc acctgcggca tcgcccagac ctactccaca 4800

catggctaca atatctggcg ggaccccatg aagcccagcc agatcctgac ccgcctctgc 4860

aaagacggca aagtggacgg cccccacttt gggccccctg ggagagtgaa ggtggccaac 4920

cgcgtcttca ctgggccctc tgagattgag gacgagaacg gtcagaggaa gcccacagac 4980

gagcatgtgg cgctgttggc cctgaggcac tgggaggaca tcccccgcgc aggctgccgc 5040

ctggtgccag agcatgtgga gacgaggccg ctgctcaacc ccgacaagcc gggcatcgag 5100

cagggccgcc tggagctgtg ggtggacatg ttccccatgg acatgccagc ccctgggacg 5160

cctctggaca tctcacctcg gaagcccaag aagtacgagc tgcgggtcat catctggaac 5220

acagatgagg tggtcttgga ggacgacgac ttcttcacag gggagaagtc cagtgacatc 5280

ttcgtgaggg ggtggctgaa gggccagcag gaggacaagc aggacacaga cgtccactac 5340

cactccctca ctggcgaggg caacttcaac tggcgctacc tgttcccctt cgactacctg 5400

gcggcggagg agaagatcgt catctccaag aaggagtcca tgttctcctg ggacgagacc 5460

gagtacaaga tccccgcgcg gctcaccctg cagatctggg atgcggacca cttctccgct 5520

gacgacttcc tgggggccat cgagctggac ctgaaccggt tcccgcgggg cgcaaagaca 5580

gccaagcagt gcaccatgga gatggccacc ggggaggtgg acgtgcccct cgtgtccatc 5640

ttcaagcaaa agcgcgtcaa aggctggtgg cccctcctgg cccgcaatga gaacgatgag 5700

tttgagctca cgggcaaggt ggaggctgag ctgcatttac tgacagcaga ggaggcagag 5760

aagaacccag tgggcctggc ccgcaatgaa cctgaccccc tagagaaacc caaccggccc 5820

gacacggcct tcgtctggtt cctcaaccct ctcaagtcca tcaagtacct catctgcacc 5880

cggtacaagt ggctcatcat caagatcgtg ctggcgctgt tggggctgct catgttgggg 5940

ctcttcctct acagcctccc tggctacatg gtcaaaaagc tccttggggc atga 5994

<210> 3

<211> 1997

<212> PRT

<213> 智人（Homo sapiens）

<400> 3

Met Ala Leu Leu Ile His Leu Lys Thr Val Ser Glu Leu Arg Gly Arg

1 5 10 15

Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser

20 25 30

Arg Val Leu Glu Asn Cys Glu Asp Val Ala Asp Phe Asp Glu Thr Phe

35 40 45

Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Met Leu Glu Ile

50 55 60

Gln Val Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr

65 70 75 80

Phe Arg Met Val Leu Gln Lys Val Val Glu Glu Ser His Val Glu Val

85 90 95

Thr Asp Thr Leu Ile Asp Asp Asn Asn Ala Ile Ile Lys Thr Ser Leu

100 105 110

Cys Val Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Ser Trp

115 120 125

Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Glu Lys

130 135 140

Asp Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Ser

145 150 155 160

Arg Pro Pro Gly Glu Lys Ser Phe Arg Arg Ala Gly Arg Ser Val Phe

165 170 175

Ser Ala Met Lys Leu Gly Lys Asn Arg Ser His Lys Glu Glu Pro Gln

180 185 190

Arg Pro Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu

195 200 205

Ala Ile Arg Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala

210 215 220

Ser Val Thr Ala Leu Thr Thr Asn Val Ser Asn Lys Arg Ser Lys Pro

225 230 235 240

Asp Ile Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val

245 250 255

Ser Ile Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp

260 265 270

Pro Val Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met

275 280 285

Lys Glu Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp

290 295 300

Phe His Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser

305 310 315 320

Val Ile His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser

325 330 335

Phe Lys Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe

340 345 350

His His Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ser Gly

355 360 365

Leu Lys Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp

370 375 380

Asn Ile Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile

385 390 395 400

Glu Gly Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp

405 410 415

Ala Arg Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met

420 425 430

Asn Thr Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn

435 440 445

Lys Asp Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys

450 455 460

Gly Lys Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu

465 470 475 480

Gln Val Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys

485 490 495

Val Gln Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr

500 505 510

His Phe Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe

515 520 525

Leu Pro Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg

530 535 540

Asn Tyr Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly

545 550 555 560

Glu Gly Val Ser Phe Arg Ala Arg Leu Leu Leu Gly Leu Ala Val Glu

565 570 575

Ile Val Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln

580 585 590

Val Glu Gln Ala Thr Pro Ile Ser Glu Ser Cys Ala Gly Lys Met Glu

595 600 605

Glu Phe Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg

610 615 620

Arg Asn Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr

625 630 635 640

Gly Asn Glu Val Asp Gly Leu Ser Arg Pro Gln Arg Pro Arg Pro Arg

645 650 655

Lys Glu Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ala Ser

660 665 670

Asp Asp Glu Ala Gly Asp Ala Gly Asp Leu Ala Ser Val Ser Ser Thr

675 680 685

Pro Pro Met Arg Pro Gln Val Thr Asp Arg Asn Tyr Phe His Leu Pro

690 695 700

Tyr Leu Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp

705 710 715 720

Gln Arg Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp

725 730 735

Lys Leu Glu Glu Gly Leu Asn Asp Ile Gln Glu Met Ile Lys Thr Glu

740 745 750

Lys Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser

755 760 765

Cys Gly Cys Cys Arg Phe Leu Ser Leu Ala Asp Lys Asp Gln Gly His

770 775 780

Ser Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg

785 790 795 800

Glu Leu Glu Asn Met Gly Gln Gln Ala Arg Met Leu Arg Ala Gln Val

805 810 815

Lys Arg His Thr Val Arg Asp Lys Leu Arg Leu Cys Gln Asn Phe Leu

820 825 830

Gln Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp

835 840 845

Ile Phe Ile Trp Met Met Ser Asn Asn Lys Arg Val Ala Tyr Ala Arg

850 855 860

Val Pro Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Thr Gly

865 870 875 880

Lys Asp Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys

885 890 895

Arg Gly Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Val Glu Leu

900 905 910

Tyr Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys Glu Phe Leu Cys Gly

915 920 925

Leu Pro Cys Gly Phe Gln Glu Val Lys Ala Ala Gln Gly Leu Gly Leu

930 935 940

His Ala Phe Pro Pro Val Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe

945 950 955 960

Gln Leu Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp

965 970 975

Ser Ser Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln

980 985 990

Ser Gln Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp

995 1000 1005

Gln Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His

1010 1015 1020

Glu Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp

1025 1030 1035

Gln Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala

1040 1045 1050

Lys Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg

1055 1060 1065

Phe Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala

1070 1075 1080

Thr Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly

1085 1090 1095

Pro Ala Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp

1100 1105 1110

Val Asp Arg Gly Pro Ile Met Pro Val Pro Met Gly Ile Arg Pro

1115 1120 1125

Val Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg

1130 1135 1140

Asp Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val

1145 1150 1155

Asp Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His

1160 1165 1170

Asn Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe

1175 1180 1185

Glu Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn

1190 1195 1200

Ile Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val

1205 1210 1215

Gly Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro

1220 1225 1230

Pro Asp Arg Ser Ala Pro Ser Trp Asn Thr Thr Val Arg Leu Leu

1235 1240 1245

Arg Arg Cys Arg Val Leu Cys Asn Gly Gly Ser Ser Ser His Ser

1250 1255 1260

Thr Gly Glu Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys

1265 1270 1275

Lys Leu Glu Thr Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val

1280 1285 1290

Val Lys Val Asp Val Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys

1295 1300 1305

Lys Lys Gly Thr Ala Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu

1310 1315 1320

Ser Met Leu Asp Trp Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr

1325 1330 1335

Met Lys Glu Gln Leu Arg Gln Gln Glu Pro Ser Gly Ile Asp Leu

1340 1345 1350

Glu Glu Lys Glu Glu Val Asp Asn Thr Glu Gly Leu Lys Gly Ser

1355 1360 1365

Met Lys Gly Lys Glu Lys Ala Arg Ala Ala Lys Glu Glu Lys Lys

1370 1375 1380

Lys Lys Thr Gln Ser Ser Gly Ser Gly Gln Gly Ser Glu Ala Pro

1385 1390 1395

Glu Lys Lys Lys Pro Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys

1400 1405 1410

Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu Asp Trp Leu His Thr

1415 1420 1425

Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser

1430 1435 1440

Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly Ser Leu Cys

1445 1450 1455

Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu Ala Gly

1460 1465 1470

Tyr Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn Asp

1475 1480 1485

Pro Ile Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp

1490 1495 1500

Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala

1505 1510 1515

Ile Arg Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile

1520 1525 1530

Ser Lys Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu

1535 1540 1545

Ala Ser Phe Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp

1550 1555 1560

Trp Asp Leu Val Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile

1565 1570 1575

Asp Leu Glu Asn Arg Phe Tyr Ser Lys His Arg Ala Thr Cys Gly

1580 1585 1590

Ile Ala Gln Thr Tyr Ser Thr His Gly Tyr Asn Ile Trp Arg Asp

1595 1600 1605

Pro Met Lys Pro Ser Gln Ile Leu Thr Arg Leu Cys Lys Asp Gly

1610 1615 1620

Lys Val Asp Gly Pro His Phe Gly Pro Pro Gly Arg Val Lys Val

1625 1630 1635

Ala Asn Arg Val Phe Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn

1640 1645 1650

Gly Gln Arg Lys Pro Thr Asp Glu His Val Ala Leu Leu Ala Leu

1655 1660 1665

Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys Arg Leu Val Pro

1670 1675 1680

Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly

1685 1690 1695

Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe Pro Met

1700 1705 1710

Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys

1715 1720 1725

Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu

1730 1735 1740

Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser

1745 1750 1755

Asp Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys

1760 1765 1770

Gln Asp Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn

1775 1780 1785

Phe Asn Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu

1790 1795 1800

Glu Lys Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp

1805 1810 1815

Glu Thr Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp

1820 1825 1830

Asp Ala Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu

1835 1840 1845

Leu Asp Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln

1850 1855 1860

Cys Thr Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val

1865 1870 1875

Ser Ile Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu

1880 1885 1890

Ala Arg Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu

1895 1900 1905

Ala Glu Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro

1910 1915 1920

Val Gly Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn

1925 1930 1935

Arg Pro Asp Thr Ser Phe Ile Trp Phe Leu Asn Pro Leu Lys Ser

1940 1945 1950

Ala Arg Tyr Phe Leu Trp His Thr Tyr Arg Trp Leu Leu Leu Lys

1955 1960 1965

Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Ala Leu Phe Leu

1970 1975 1980

Tyr Ser Val Pro Gly Tyr Leu Val Lys Lys Ile Leu Gly Ala

1985 1990 1995

<210> 4

<211> 5994

<212> DNA

<213> 智人（Homo sapiens）

<400> 4

atggccttgc tcatccacct caagacagtc tcggagctgc ggggcagggg cgaccggatc 60

gccaaagtga ctttccgagg gcaatccttc tactctcggg tcctggagaa ctgtgaggat 120

gtggctgact ttgatgagac atttcggtgg ccggtggcca gcagcatcga cagaaatgag 180

atgctggaga ttcaggtttt caactacagc aaagtcttca gcaacaagct catcgggacc 240

ttccgcatgg tgctgcagaa ggtggtagag gagagccatg tggaggtgac tgacacgctg 300

attgatgaca acaatgctat catcaagacc agcctgtgcg tggaggtccg gtatcaggcc 360

actgacggca cagtgggctc ctgggacgat ggggacttcc tgggagatga gtctcttcaa 420

gaggaagaga aggacagcca agagacggat ggactgctcc caggctcccg gcccagctcc 480

cggcccccag gagagaagag cttccggaga gccgggagga gcgtgttctc cgccatgaag 540

ctcggcaaaa accggtctca caaggaggag ccccaaagac cagatgaacc ggcggtgctg 600

gagatggaag accttgacca tctggccatt cggctaggag atggactgga tcccgactcg 660

gtgtctctag cctcagtcac agctctcacc actaatgtct ccaacaagcg atctaagcca 720

gacattaaga tggagccaag tgctgggcgg cccatggatt accaggtcag catcacggtg 780

atcgaggccc ggcagctggt gggcttgaac atggaccctg tggtgtgcgt ggaggtgggt 840

gacgacaaga agtacacatc catgaaggag tccactaact gcccctatta caacgagtac 900

ttcgtcttcg acttccatgt ctctccggat gtcatgtttg acaagatcat caagatttcg 960

gtgattcact ccaagaacct gctgcgcagt ggcaccctgg tgggctcctt caaaatggac 1020

gtgggaaccg tgtactcgca gccagagcac cagttccatc acaagtgggc catcctgtct 1080

gaccccgatg acatctcctc ggggctgaag ggctacgtga agtgtgacgt tgccgtggtg 1140

ggcaaagggg acaacatcaa gacgccccac aaggccaatg agaccgacga agatgacatt 1200

gaggggaact tgctgctccc cgagggggtg ccccccgaac gccagtgggc ccggttctat 1260

gtgaaaattt accgagcaga ggggctgccc cgtatgaaca caagcctcat ggccaatgta 1320

aagaaggctt tcatcggtga aaacaaggac ctcgtggacc cctacgtgca agtcttcttt 1380

gctggccaga agggcaagac ttcagtgcag aagagcagct atgagcccct gtggaatgag 1440

caggtcgtct ttacagacct cttcccccca ctctgcaaac gcatgaaggt gcagatccga 1500

gactcggaca aggtcaacga cgtggccatc ggcacccact tcattgacct gcgcaagatt 1560

tctaatgacg gagacaaagg cttcctgccc acactgggcc cagcctgggt gaacatgtac 1620

ggctccacac gtaactacac gctgctggat gagcatcagg acctgaacga gggcctgggg 1680

gagggtgtgt ccttccgggc ccggctcctg ctgggcctgg ctgtggagat cgtagacacc 1740

tccaaccctg agctcaccag ctccacagag gtgcaggtgg agcaggccac gcccatctcg 1800

gagagctgtg caggtaaaat ggaagaattc tttctctttg gagccttcct ggaggcctca 1860

atgatcgacc ggagaaacgg agacaagccc atcacctttg aggtcaccat aggcaactat 1920

gggaacgaag ttgatggcct gtcccggccc cagcggcctc ggccccggaa ggagccgggg 1980

gatgaggaag aagtagacct gattcagaac gcaagtgatg acgaggccgg tgatgccggg 2040

gacctggcct cagtctcctc cactccacca atgcggcccc aggtcaccga caggaactac 2100

ttccatctgc cctacctgga gcgaaagccc tgcatctaca tcaagagctg gtggccggac 2160

cagcgccgcc gcctctacaa tgccaacatc atggaccaca ttgccgacaa gctggaagaa 2220

ggcctgaacg acatacagga gatgatcaaa acggagaagt cctaccctga gcgtcgcctg 2280

cggggcgtcc tggaggagct gagctgtggc tgctgccgct tcctctccct cgctgacaag 2340

gaccagggcc actcatcccg caccaggctt gaccgggagc gcctcaagtc ctgcatgagg 2400

gagctggaaa acatggggca gcaggccagg atgctgcggg cccaggtgaa gcggcacacg 2460

gtgcgggaca agctgaggct gtgccagaac ttcctgcaga agctgcgctt cctggcggac 2520

gagccccagc acagcattcc cgacatcttc atctggatga tgagcaacaa caagcgtgtc 2580

gcctatgccc gtgtgccctc caaggacctg ctcttctcca tcgtggagga ggagactggc 2640

aaggactgcg ccaaggtcaa gacgctcttc cttaagctgc cagggaagcg gggcttcggc 2700

tcggcaggct ggacagtgca ggccaaggtg gagctgtacc tgtggctggg cctcagcaaa 2760

cagcgcaagg agttcctgtg cggcctgccc tgtggcttcc aggaggtcaa ggcagcccag 2820

ggcctgggcc tgcatgcctt cccacccgtc agcctggtct acaccaagaa gcaggcgttc 2880

cagctccgag cgcacatgta ccaggcccgc agcctctttg ccgccgacag cagcggactc 2940

tcagacccct ttgcccgcgt cttcttcatc aatcagagtc agtgcacaga ggtgctgaat 3000

gagaccctgt gtcccacctg ggaccagatg ctggtgttcg acaacctgga gctctatggt 3060

gaagctcatg agctgaggga cgatccgccc atcattgtca ttgaaatcta tgaccaggat 3120

tccatgggca aagctgactt catgggccgg accttcgcca aacccctggt gaagatggca 3180

gacgaggcgt actgcccacc ccgcttccca cctcagctcg agtactacca gatctaccgt 3240

ggcaacgcca cagctggaga cctgctggcg gccttcgagc tgctgcagat tggaccagca 3300

gggaaggctg acctgccccc catcaatggc ccggtggacg tggaccgagg tcccatcatg 3360

cccgtgccca tgggcatccg gcccgtgctc agcaagtacc gagtggaggt gctgttctgg 3420

ggcctacggg acctaaagcg ggtgaacctg gcccaggtgg accggccacg ggtggacatc 3480

gagtgtgcag ggaagggggt gcagtcgtcc ctgatccaca attataagaa gaaccccaac 3540

ttcaacaccc tcgtcaagtg gtttgaagtg gacctcccag agaacgagct gctgcacccg 3600

cccttgaaca tccgtgtggt ggactgccgg gccttcggtc gctacacact ggtgggctcc 3660

catgccgtca gctccctgcg acgcttcatc taccggcccc cagaccgctc ggcccccagc 3720

tggaacacca cggtcaggct tctccggcgc tgccgtgtgc tgtgcaatgg gggctcctcc 3780

tctcactcca caggggaggt tgtggtgact atggagccag aggtacccat caagaaactg 3840

gagaccatgg tgaagctgga cgcgacttct gaagctgttg tcaaggtgga tgtggctgag 3900

gaggagaagg agaagaagaa gaagaagaag ggcactgcgg aggagccaga ggaggaggag 3960

ccagacgaga gcatgctgga ctggtggtcc aagtactttg cctccattga caccatgaag 4020

gagcaacttc gacaacaaga gccctctgga attgacttgg aggagaagga ggaagtggac 4080

aataccgagg gcctgaaggg gtcaatgaag ggcaaggaga aggcaagggc tgccaaagag 4140

gagaagaaga agaaaactca gagctctggc tctggccagg ggtccgaggc ccccgagaag 4200

aagaaaccca agattgatga gcttaaggta taccccaaag agctggagtc cgagtttgat 4260

aactttgagg actggctgca cactttcaac ttgcttcggg gcaagaccgg ggatgatgag 4320

gatggctcca ccgaggagga gcgcattgtg ggacgcttca agggctccct ctgcgtgtac 4380

aaagtgccac tcccagagga cgtgtcccgg gaagccggct acgactccac ctacggcatg 4440

ttccagggca tcccgagcaa tgaccccatc aatgtgctgg tccgagtcta tgtggtccgg 4500

gccacggacc tgcaccctgc tgacatcaac ggcaaagctg acccctacat cgccatccgg 4560

ctaggcaaga ctgacatccg cgacaaggag aactacatct ccaagcagct caaccctgtc 4620

tttgggaagt cctttgacat cgaggcctcc ttccccatgg aatccatgct gacggtggct 4680

gtgtatgact gggacctggt gggcactgat gacctcattg gggaaaccaa gatcgacctg 4740

gagaaccgct tctacagcaa gcaccgcgcc acctgcggca tcgcccagac ctactccaca 4800

catggctaca atatctggcg ggaccccatg aagcccagcc agatcctgac ccgcctctgc 4860

aaagacggca aagtggacgg cccccacttt gggccccctg ggagagtgaa ggtggccaac 4920

cgcgtcttca ctgggccctc tgagattgag gacgagaacg gtcagaggaa gcccacagac 4980

gagcatgtgg cgctgttggc cctgaggcac tgggaggaca tcccccgcgc aggctgccgc 5040

ctggtgccag agcatgtgga gacgaggccg ctgctcaacc ccgacaagcc gggcatcgag 5100

cagggccgcc tggagctgtg ggtggacatg ttccccatgg acatgccagc ccctgggacg 5160

cctctggaca tctcacctcg gaagcccaag aagtacgagc tgcgggtcat catctggaac 5220

acagatgagg tggtcttgga ggacgacgac ttcttcacag gggagaagtc cagtgacatc 5280

ttcgtgaggg ggtggctgaa gggccagcag gaggacaagc aggacacaga cgtccactac 5340

cactccctca ctggcgaggg caacttcaac tggcgctacc tgttcccctt cgactacctg 5400

gcggcggagg agaagatcgt catctccaag aaggagtcca tgttctcctg ggacgagacc 5460

gagtacaaga tccccgcgcg gctcaccctg cagatctggg atgcggacca cttctccgct 5520

gacgacttcc tgggggccat cgagctggac ctgaaccggt tcccgcgggg cgcaaagaca 5580

gccaagcagt gcaccatgga gatggccacc ggggaggtgg acgtgcccct cgtgtccatc 5640

ttcaagcaaa agcgcgtcaa aggctggtgg cccctcctgg cccgcaatga gaacgatgag 5700

tttgagctca cgggcaaggt ggaggctgag ctgcatttac tgacagcaga ggaggcagag 5760

aagaacccag tgggcctggc ccgcaatgaa cctgaccccc tagagaaacc caaccggccc 5820

gacacgagct tcatctggtt cctgaaccct ctcaagtcgg ctcgctactt cttgtggcac 5880

acgtatcgct ggctgctcct caaactgttg ctgctcctgc tgctgctcct cctcctcgcc 5940

ctgttcctct actctgtgcc tggctacctg gtcaagaaaa tcctcggggc ctga 5994

<210> 5

<211> 1230

<212> PRT

<213> 智人（Homo sapiens）

<400> 5

Met Ile Lys Thr Glu Lys Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val

1 5 10 15

Leu Glu Glu Leu Ser Cys Gly Cys Cys Arg Phe Leu Ser Leu Ala Asp

20 25 30

Lys Asp Gln Gly His Ser Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu

35 40 45

Lys Ser Cys Met Arg Glu Leu Glu Asn Met Gly Gln Gln Ala Arg Met

50 55 60

Leu Arg Ala Gln Val Lys Arg His Thr Val Arg Asp Lys Leu Arg Leu

65 70 75 80

Cys Gln Asn Phe Leu Gln Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln

85 90 95

His Ser Ile Pro Asp Ile Phe Ile Trp Met Met Ser Asn Asn Lys Arg

100 105 110

Val Ala Tyr Ala Arg Val Pro Ser Lys Asp Leu Leu Phe Ser Ile Val

115 120 125

Glu Glu Glu Thr Gly Lys Asp Cys Ala Lys Val Lys Thr Leu Phe Leu

130 135 140

Lys Leu Pro Gly Lys Arg Gly Phe Gly Ser Ala Gly Trp Thr Val Gln

145 150 155 160

Ala Lys Val Glu Leu Tyr Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys

165 170 175

Glu Phe Leu Cys Gly Leu Pro Cys Gly Phe Gln Glu Val Lys Ala Ala

180 185 190

Gln Gly Leu Gly Leu His Ala Phe Pro Pro Val Ser Leu Val Tyr Thr

195 200 205

Lys Lys Gln Ala Phe Gln Leu Arg Ala His Met Tyr Gln Ala Arg Ser

210 215 220

Leu Phe Ala Ala Asp Ser Ser Gly Leu Ser Asp Pro Phe Ala Arg Val

225 230 235 240

Phe Phe Ile Asn Gln Ser Gln Cys Thr Glu Val Leu Asn Glu Thr Leu

245 250 255

Cys Pro Thr Trp Asp Gln Met Leu Val Phe Asp Asn Leu Glu Leu Tyr

260 265 270

Gly Glu Ala His Glu Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu

275 280 285

Ile Tyr Asp Gln Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr

290 295 300

Phe Ala Lys Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro

305 310 315 320

Arg Phe Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala

325 330 335

Thr Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro

340 345 350

Ala Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Val Asp

355 360 365

Arg Gly Pro Ile Met Pro Val Pro Met Gly Ile Arg Pro Val Leu Ser

370 375 380

Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp Leu Lys Arg

385 390 395 400

Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp Ile Glu Cys Ala

405 410 415

Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn Tyr Lys Lys Asn Pro

420 425 430

Asn Phe Asn Thr Leu Val Lys Trp Phe Glu Val Asp Leu Pro Glu Asn

435 440 445

Glu Leu Leu His Pro Pro Leu Asn Ile Arg Val Val Asp Cys Arg Ala

450 455 460

Phe Gly Arg Tyr Thr Leu Val Gly Ser His Ala Val Ser Ser Leu Arg

465 470 475 480

Arg Phe Ile Tyr Arg Pro Pro Asp Arg Ser Ala Pro Ser Trp Asn Thr

485 490 495

Thr Gly Glu Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys Lys

500 505 510

Leu Glu Thr Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val Val Lys

515 520 525

Val Asp Val Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys Lys Lys Gly

530 535 540

Thr Ala Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp

545 550 555 560

Trp Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu

565 570 575

Arg Gln Gln Glu Pro Ser Gly Ile Asp Leu Glu Glu Lys Glu Glu Val

580 585 590

Asp Asn Thr Glu Gly Leu Lys Gly Ser Met Lys Gly Lys Glu Lys Ala

595 600 605

Arg Ala Ala Lys Glu Glu Lys Lys Lys Lys Thr Gln Ser Ser Gly Ser

610 615 620

Gly Gln Gly Ser Glu Ala Pro Glu Lys Lys Lys Pro Lys Ile Asp Glu

625 630 635 640

Leu Lys Val Tyr Pro Lys Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu

645 650 655

Asp Trp Leu His Thr Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp

660 665 670

Glu Asp Gly Ser Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly

675 680 685

Ser Leu Cys Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu

690 695 700

Ala Gly Tyr Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn

705 710 715 720

Asp Pro Ile Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp

725 730 735

Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile

740 745 750

Arg Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys

755 760 765

Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe

770 775 780

Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val

785 790 795 800

Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg

805 810 815

Phe Tyr Ser Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr Ser

820 825 830

Thr His Gly Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser Gln Ile

835 840 845

Leu Thr Arg Leu Cys Lys Asp Gly Lys Val Asp Gly Pro His Phe Gly

850 855 860

Pro Pro Gly Arg Val Lys Val Ala Asn Arg Val Phe Thr Gly Pro Ser

865 870 875 880

Glu Ile Glu Asp Glu Asn Gly Gln Arg Lys Pro Thr Asp Glu His Val

885 890 895

Ala Leu Leu Ala Leu Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys

900 905 910

Arg Leu Val Pro Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp

915 920 925

Lys Pro Gly Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe

930 935 940

Pro Met Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg

945 950 955 960

Lys Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu

965 970 975

Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser Asp

980 985 990

Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys Gln Asp

995 1000 1005

Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn Phe Asn

1010 1015 1020

Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu Glu Lys

1025 1030 1035

Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp Glu Thr

1040 1045 1050

Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp Asp Ala

1055 1060 1065

Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu Leu Asp

1070 1075 1080

Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln Cys Thr

1085 1090 1095

Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val Ser Ile

1100 1105 1110

Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu Ala Arg

1115 1120 1125

Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu Ala Glu

1130 1135 1140

Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro Val Gly

1145 1150 1155

Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn Arg Pro

1160 1165 1170

Asp Thr Ser Phe Ile Trp Phe Leu Asn Pro Leu Lys Ser Ala Arg

1175 1180 1185

Tyr Phe Leu Trp His Thr Tyr Arg Trp Leu Leu Leu Lys Leu Leu

1190 1195 1200

Leu Leu Leu Leu Leu Leu Leu Leu Leu Ala Leu Phe Leu Tyr Ser

1205 1210 1215

Val Pro Gly Tyr Leu Val Lys Lys Ile Leu Gly Ala

1220 1225 1230

<210> 6

<211> 3693

<212> DNA

<213> 智人（Homo sapiens）

<400> 6

atgatcaaaa cggagaagtc ctaccctgag cgtcgcctgc ggggcgtcct ggaggagctg 60

agctgtggct gctgccgctt cctctccctc gctgacaagg accagggcca ctcatcccgc 120

accaggcttg accgggagcg cctcaagtcc tgcatgaggg agctggaaaa catggggcag 180

caggccagga tgctgcgggc ccaggtgaag cggcacacgg tgcgggacaa gctgaggctg 240

tgccagaact tcctgcagaa gctgcgcttc ctggcggacg agccccagca cagcattccc 300

gacatcttca tctggatgat gagcaacaac aagcgtgtcg cctatgcccg tgtgccctcc 360

aaggacctgc tcttctccat cgtggaggag gagactggca aggactgcgc caaggtcaag 420

acgctcttcc ttaagctgcc agggaagcgg ggcttcggct cggcaggctg gacagtgcag 480

gccaaggtgg agctgtacct gtggctgggc ctcagcaaac agcgcaagga gttcctgtgc 540

ggcctgccct gtggcttcca ggaggtcaag gcagcccagg gcctgggcct gcatgccttc 600

ccacccgtca gcctggtcta caccaagaag caggcgttcc agctccgagc gcacatgtac 660

caggcccgca gcctctttgc cgccgacagc agcggactct cagacccctt tgcccgcgtc 720

ttcttcatca atcagagtca gtgcacagag gtgctgaatg agaccctgtg tcccacctgg 780

gaccagatgc tggtgttcga caacctggag ctctatggtg aagctcatga gctgagggac 840

gatccgccca tcattgtcat tgaaatctat gaccaggatt ccatgggcaa agctgacttc 900

atgggccgga ccttcgccaa acccctggtg aagatggcag acgaggcgta ctgcccaccc 960

cgcttcccac ctcagctcga gtactaccag atctaccgtg gcaacgccac agctggagac 1020

ctgctggcgg ccttcgagct gctgcagatt ggaccagcag ggaaggctga cctgcccccc 1080

atcaatggcc cggtggacgt ggaccgaggt cccatcatgc ccgtgcccat gggcatccgg 1140

cccgtgctca gcaagtaccg agtggaggtg ctgttctggg gcctacggga cctaaagcgg 1200

gtgaacctgg cccaggtgga ccggccacgg gtggacatcg agtgtgcagg gaagggggtg 1260

cagtcgtccc tgatccacaa ttataagaag aaccccaact tcaacaccct cgtcaagtgg 1320

tttgaagtgg acctcccaga gaacgagctg ctgcacccgc ccttgaacat ccgtgtggtg 1380

gactgccggg ccttcggtcg ctacacactg gtgggctccc atgccgtcag ctccctgcga 1440

cgcttcatct accggccccc agaccgctcg gcccccagct ggaacaccac gggggaggtt 1500

gtggtgacta tggagccaga ggtacccatc aagaaactgg agaccatggt gaagctggac 1560

gcgacttctg aagctgttgt caaggtggat gtggctgagg aggagaagga gaagaagaag 1620

aagaagaagg gcactgcgga ggagccagag gaggaggagc cagacgagag catgctggac 1680

tggtggtcca agtactttgc ctccattgac accatgaagg agcaacttcg acaacaagag 1740

ccctctggaa ttgacttgga ggagaaggag gaagtggaca ataccgaggg cctgaagggg 1800

tcaatgaagg gcaaggagaa ggcaagggct gccaaagagg agaagaagaa gaaaactcag 1860

agctctggct ctggccaggg gtccgaggcc cccgagaaga agaaacccaa gattgatgag 1920

cttaaggtat accccaaaga gctggagtcc gagtttgata actttgagga ctggctgcac 1980

actttcaact tgcttcgggg caagaccggg gatgatgagg atggctccac cgaggaggag 2040

cgcattgtgg gacgcttcaa gggctccctc tgcgtgtaca aagtgccact cccagaggac 2100

gtgtcccggg aagccggcta cgactccacc tacggcatgt tccagggcat cccgagcaat 2160

gaccccatca atgtgctggt ccgagtctat gtggtccggg ccacggacct gcaccctgct 2220

gacatcaacg gcaaagctga cccctacatc gccatccggc taggcaagac tgacatccgc 2280

gacaaggaga actacatctc caagcagctc aaccctgtct ttgggaagtc ctttgacatc 2340

gaggcctcct tccccatgga atccatgctg acggtggctg tgtatgactg ggacctggtg 2400

ggcactgatg acctcattgg ggaaaccaag atcgacctgg agaaccgctt ctacagcaag 2460

caccgcgcca cctgcggcat cgcccagacc tactccacac atggctacaa tatctggcgg 2520

gaccccatga agcccagcca gatcctgacc cgcctctgca aagacggcaa agtggacggc 2580

ccccactttg ggccccctgg gagagtgaag gtggccaacc gcgtcttcac tgggccctct 2640

gagattgagg acgagaacgg tcagaggaag cccacagacg agcatgtggc gctgttggcc 2700

ctgaggcact gggaggacat cccccgcgca ggctgccgcc tggtgccaga gcatgtggag 2760

acgaggccgc tgctcaaccc cgacaagccg ggcatcgagc agggccgcct ggagctgtgg 2820

gtggacatgt tccccatgga catgccagcc cctgggacgc ctctggacat ctcacctcgg 2880

aagcccaaga agtacgagct gcgggtcatc atctggaaca cagatgaggt ggtcttggag 2940

gacgacgact tcttcacagg ggagaagtcc agtgacatct tcgtgagggg gtggctgaag 3000

ggccagcagg aggacaagca ggacacagac gtccactacc actccctcac tggcgagggc 3060

aacttcaact ggcgctacct gttccccttc gactacctgg cggcggagga gaagatcgtc 3120

atctccaaga aggagtccat gttctcctgg gacgagaccg agtacaagat ccccgcgcgg 3180

ctcaccctgc agatctggga tgcggaccac ttctccgctg acgacttcct gggggccatc 3240

gagctggacc tgaaccggtt cccgcggggc gcaaagacag ccaagcagtg caccatggag 3300

atggccaccg gggaggtgga cgtgcccctc gtgtccatct tcaagcaaaa gcgcgtcaaa 3360

ggctggtggc ccctcctggc ccgcaatgag aacgatgagt ttgagctcac gggcaaggtg 3420

gaggctgagc tgcatttact gacagcagag gaggcagaga agaacccagt gggcctggcc 3480

cgcaatgaac ctgaccccct agagaaaccc aaccggcccg acacgagctt catctggttc 3540

ctgaaccctc tcaagtcggc tcgctacttc ttgtggcaca cgtatcgctg gctgctcctc 3600

aaactgttgc tgctcctgct gctgctcctc ctcctcgccc tgttcctcta ctctgtgcct 3660

ggctacctgg tcaagaaaat cctcggggcc tga 3693

<210> 7

<211> 1307

<212> PRT

<213> 智人（Homo sapiens）

<400> 7

Met Met Thr Asp Thr Gln Asp Gly Pro Ser Glu Ser Ser Gln Ile Met

1 5 10 15

Arg Ser Leu Thr Pro Leu Ile Asn Arg Glu Glu Ala Phe Gly Glu Ala

20 25 30

Gly Glu Ala Gly Leu Trp Pro Ser Ile Thr His Thr Pro Asp Ser Gln

35 40 45

Glu Glu Gly Leu Asn Asp Ile Gln Glu Met Ile Lys Thr Glu Lys Ser

50 55 60

Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser Cys Gly

65 70 75 80

Cys Cys Arg Phe Leu Ser Leu Ala Asp Lys Asp Gln Gly His Ser Ser

85 90 95

Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg Glu Leu

100 105 110

Glu Asn Met Gly Gln Gln Ala Arg Met Leu Arg Ala Gln Val Lys Arg

115 120 125

His Thr Val Arg Asp Lys Leu Arg Leu Cys Gln Asn Phe Leu Gln Lys

130 135 140

Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp Ile Phe

145 150 155 160

Ile Trp Met Met Ser Asn Asn Lys Arg Val Ala Tyr Ala Arg Val Pro

165 170 175

Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Thr Gly Lys Asp

180 185 190

Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys Arg Gly

195 200 205

Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Val Glu Leu Tyr Leu

210 215 220

Trp Leu Gly Leu Ser Lys Gln Arg Lys Glu Phe Leu Cys Gly Leu Pro

225 230 235 240

Cys Gly Phe Gln Glu Val Lys Ala Ala Gln Gly Leu Gly Leu His Ala

245 250 255

Phe Pro Pro Val Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe Gln Leu

260 265 270

Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp Ser Ser

275 280 285

Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln Ser Gln

290 295 300

Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp Gln Met

305 310 315 320

Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His Glu Leu Arg

325 330 335

Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp Gln Asp Ser Met

340 345 350

Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala Lys Pro Leu Val Lys

355 360 365

Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg Phe Pro Pro Gln Leu Glu

370 375 380

Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala Thr Ala Gly Asp Leu Leu Ala

385 390 395 400

Ala Phe Glu Leu Leu Gln Ile Gly Pro Ala Gly Lys Ala Asp Leu Pro

405 410 415

Pro Ile Asn Gly Pro Val Asp Val Asp Arg Gly Pro Ile Met Pro Val

420 425 430

Pro Met Gly Ile Arg Pro Val Leu Ser Lys Tyr Arg Val Glu Val Leu

435 440 445

Phe Trp Gly Leu Arg Asp Leu Lys Arg Val Asn Leu Ala Gln Val Asp

450 455 460

Arg Pro Arg Val Asp Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser

465 470 475 480

Leu Ile His Asn Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys

485 490 495

Trp Phe Glu Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu

500 505 510

Asn Ile Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val

515 520 525

Gly Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro Pro

530 535 540

Asp Arg Ser Ala Pro Ser Trp Asn Thr Thr Val Arg Leu Leu Arg Arg

545 550 555 560

Cys Arg Val Leu Cys Asn Gly Gly Ser Ser Ser His Ser Thr Gly Glu

565 570 575

Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys Lys Leu Glu Thr

580 585 590

Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val Val Lys Val Asp Val

595 600 605

Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys Lys Lys Gly Thr Ala Glu

610 615 620

Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp Trp Trp Ser

625 630 635 640

Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu Arg Gln Gln

645 650 655

Glu Pro Ser Gly Ile Asp Leu Glu Glu Lys Glu Glu Val Asp Asn Thr

660 665 670

Glu Gly Leu Lys Gly Ser Met Lys Gly Lys Glu Lys Ala Arg Ala Ala

675 680 685

Lys Glu Glu Lys Lys Lys Lys Thr Gln Ser Ser Gly Ser Gly Gln Gly

690 695 700

Ser Glu Ala Pro Glu Lys Lys Lys Pro Lys Ile Asp Glu Leu Lys Val

705 710 715 720

Tyr Pro Lys Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu Asp Trp Leu

725 730 735

His Thr Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp Glu Asp Gly

740 745 750

Ser Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly Ser Leu Cys

755 760 765

Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu Ala Gly Tyr

770 775 780

Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn Asp Pro Ile

785 790 795 800

Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp Leu His Pro

805 810 815

Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile Arg Leu Gly

820 825 830

Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys Gln Leu Asn

835 840 845

Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe Pro Met Glu

850 855 860

Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val Gly Thr Asp

865 870 875 880

Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg Phe Tyr Ser

885 890 895

Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr Ser Thr His Gly

900 905 910

Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser Gln Ile Leu Thr Arg

915 920 925

Leu Cys Lys Asp Gly Lys Val Asp Gly Pro His Phe Gly Pro Pro Gly

930 935 940

Arg Val Lys Val Ala Asn Arg Val Phe Thr Gly Pro Ser Glu Ile Glu

945 950 955 960

Asp Glu Asn Gly Gln Arg Lys Pro Thr Asp Glu His Val Ala Leu Leu

965 970 975

Ala Leu Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys Arg Leu Val

980 985 990

Pro Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly

995 1000 1005

Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe Pro Met

1010 1015 1020

Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys

1025 1030 1035

Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu

1040 1045 1050

Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser

1055 1060 1065

Asp Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys

1070 1075 1080

Gln Asp Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn

1085 1090 1095

Phe Asn Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu

1100 1105 1110

Glu Lys Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp

1115 1120 1125

Glu Thr Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp

1130 1135 1140

Asp Ala Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu

1145 1150 1155

Leu Asp Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln

1160 1165 1170

Cys Thr Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val

1175 1180 1185

Ser Ile Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu

1190 1195 1200

Ala Arg Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu

1205 1210 1215

Ala Glu Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro

1220 1225 1230

Val Gly Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn

1235 1240 1245

Arg Pro Asp Thr Ser Phe Ile Trp Phe Leu Asn Pro Leu Lys Ser

1250 1255 1260

Ala Arg Tyr Phe Leu Trp His Thr Tyr Arg Trp Leu Leu Leu Lys

1265 1270 1275

Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Ala Leu Phe Leu

1280 1285 1290

Tyr Ser Val Pro Gly Tyr Leu Val Lys Lys Ile Leu Gly Ala

1295 1300 1305

<210> 8

<211> 3924

<212> DNA

<213> 智人（Homo sapiens）

<400> 8

atgatgaccg atactcagga tggccctagc gagagctccc agatcatgag gtccctcact 60

cccctgatca acagggagga ggcatttggg gaggctgggg aggcggggct gtggcccagc 120

atcacccaca ctcctgattc acaggaagaa ggcctgaacg acatacagga gatgatcaaa 180

acggagaagt cctaccctga gcgtcgcctg cggggcgtcc tggaggagct gagctgtggc 240

tgctgccgct tcctctccct cgctgacaag gaccagggcc actcatcccg caccaggctt 300

gaccgggagc gcctcaagtc ctgcatgagg gagctggaaa acatggggca gcaggccagg 360

atgctgcggg cccaggtgaa gcggcacacg gtgcgggaca agctgaggct gtgccagaac 420

ttcctgcaga agctgcgctt cctggcggac gagccccagc acagcattcc cgacatcttc 480

atctggatga tgagcaacaa caagcgtgtc gcctatgccc gtgtgccctc caaggacctg 540

ctcttctcca tcgtggagga ggagactggc aaggactgcg ccaaggtcaa gacgctcttc 600

cttaagctgc cagggaagcg gggcttcggc tcggcaggct ggacagtgca ggccaaggtg 660

gagctgtacc tgtggctggg cctcagcaaa cagcgcaagg agttcctgtg cggcctgccc 720

tgtggcttcc aggaggtcaa ggcagcccag ggcctgggcc tgcatgcctt cccacccgtc 780

agcctggtct acaccaagaa gcaggcgttc cagctccgag cgcacatgta ccaggcccgc 840

agcctctttg ccgccgacag cagcggactc tcagacccct ttgcccgcgt cttcttcatc 900

aatcagagtc agtgcacaga ggtgctgaat gagaccctgt gtcccacctg ggaccagatg 960

ctggtgttcg acaacctgga gctctatggt gaagctcatg agctgaggga cgatccgccc 1020

atcattgtca ttgaaatcta tgaccaggat tccatgggca aagctgactt catgggccgg 1080

accttcgcca aacccctggt gaagatggca gacgaggcgt actgcccacc ccgcttccca 1140

cctcagctcg agtactacca gatctaccgt ggcaacgcca cagctggaga cctgctggcg 1200

gccttcgagc tgctgcagat tggaccagca gggaaggctg acctgccccc catcaatggc 1260

ccggtggacg tggaccgagg tcccatcatg cccgtgccca tgggcatccg gcccgtgctc 1320

agcaagtacc gagtggaggt gctgttctgg ggcctacggg acctaaagcg ggtgaacctg 1380

gcccaggtgg accggccacg ggtggacatc gagtgtgcag ggaagggggt gcagtcgtcc 1440

ctgatccaca attataagaa gaaccccaac ttcaacaccc tcgtcaagtg gtttgaagtg 1500

gacctcccag agaacgagct gctgcacccg cccttgaaca tccgtgtggt ggactgccgg 1560

gccttcggtc gctacacact ggtgggctcc catgccgtca gctccctgcg acgcttcatc 1620

taccggcccc cagaccgctc ggcccccagc tggaacacca cggtcaggct tctccggcgc 1680

tgccgtgtgc tgtgcaatgg gggctcctcc tctcactcca caggggaggt tgtggtgact 1740

atggagccag aggtacccat caagaaactg gagaccatgg tgaagctgga cgcgacttct 1800

gaagctgttg tcaaggtgga tgtggctgag gaggagaagg agaagaagaa gaagaagaag 1860

ggcactgcgg aggagccaga ggaggaggag ccagacgaga gcatgctgga ctggtggtcc 1920

aagtactttg cctccattga caccatgaag gagcaacttc gacaacaaga gccctctgga 1980

attgacttgg aggagaagga ggaagtggac aataccgagg gcctgaaggg gtcaatgaag 2040

ggcaaggaga aggcaagggc tgccaaagag gagaagaaga agaaaactca gagctctggc 2100

tctggccagg ggtccgaggc ccccgagaag aagaaaccca agattgatga gcttaaggta 2160

taccccaaag agctggagtc cgagtttgat aactttgagg actggctgca cactttcaac 2220

ttgcttcggg gcaagaccgg ggatgatgag gatggctcca ccgaggagga gcgcattgtg 2280

ggacgcttca agggctccct ctgcgtgtac aaagtgccac tcccagagga cgtgtcccgg 2340

gaagccggct acgactccac ctacggcatg ttccagggca tcccgagcaa tgaccccatc 2400

aatgtgctgg tccgagtcta tgtggtccgg gccacggacc tgcaccctgc tgacatcaac 2460

ggcaaagctg acccctacat cgccatccgg ctaggcaaga ctgacatccg cgacaaggag 2520

aactacatct ccaagcagct caaccctgtc tttgggaagt cctttgacat cgaggcctcc 2580

ttccccatgg aatccatgct gacggtggct gtgtatgact gggacctggt gggcactgat 2640

gacctcattg gggaaaccaa gatcgacctg gagaaccgct tctacagcaa gcaccgcgcc 2700

acctgcggca tcgcccagac ctactccaca catggctaca atatctggcg ggaccccatg 2760

aagcccagcc agatcctgac ccgcctctgc aaagacggca aagtggacgg cccccacttt 2820

gggccccctg ggagagtgaa ggtggccaac cgcgtcttca ctgggccctc tgagattgag 2880

gacgagaacg gtcagaggaa gcccacagac gagcatgtgg cgctgttggc cctgaggcac 2940

tgggaggaca tcccccgcgc aggctgccgc ctggtgccag agcatgtgga gacgaggccg 3000

ctgctcaacc ccgacaagcc gggcatcgag cagggccgcc tggagctgtg ggtggacatg 3060

ttccccatgg acatgccagc ccctgggacg cctctggaca tctcacctcg gaagcccaag 3120

aagtacgagc tgcgggtcat catctggaac acagatgagg tggtcttgga ggacgacgac 3180

ttcttcacag gggagaagtc cagtgacatc ttcgtgaggg ggtggctgaa gggccagcag 3240

gaggacaagc aggacacaga cgtccactac cactccctca ctggcgaggg caacttcaac 3300

tggcgctacc tgttcccctt cgactacctg gcggcggagg agaagatcgt catctccaag 3360

aaggagtcca tgttctcctg ggacgagacc gagtacaaga tccccgcgcg gctcaccctg 3420

cagatctggg atgcggacca cttctccgct gacgacttcc tgggggccat cgagctggac 3480

ctgaaccggt tcccgcgggg cgcaaagaca gccaagcagt gcaccatgga gatggccacc 3540

ggggaggtgg acgtgcccct cgtgtccatc ttcaagcaaa agcgcgtcaa aggctggtgg 3600

cccctcctgg cccgcaatga gaacgatgag tttgagctca cgggcaaggt ggaggctgag 3660

ctgcatttac tgacagcaga ggaggcagag aagaacccag tgggcctggc ccgcaatgaa 3720

cctgaccccc tagagaaacc caaccggccc gacacgagct tcatctggtt cctgaaccct 3780

ctcaagtcgg ctcgctactt cttgtggcac acgtatcgct ggctgctcct caaactgttg 3840

ctgctcctgc tgctgctcct cctcctcgcc ctgttcctct actctgtgcc tggctacctg 3900

gtcaagaaaa tcctcggggc ctga 3924

<210> 9

<211> 1230

<212> PRT

<213> 智人（Homo sapiens）

<400> 9

Met Ile Lys Thr Glu Lys Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val

1 5 10 15

Leu Glu Glu Leu Ser Cys Gly Cys Cys Arg Phe Leu Ser Leu Ala Asp

20 25 30

Lys Asp Gln Gly His Ser Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu

35 40 45

Lys Ser Cys Met Arg Glu Leu Glu Asn Met Gly Gln Gln Ala Arg Met

50 55 60

Leu Arg Ala Gln Val Lys Arg His Thr Val Arg Asp Lys Leu Arg Leu

65 70 75 80

Cys Gln Asn Phe Leu Gln Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln

85 90 95

His Ser Ile Pro Asp Ile Phe Ile Trp Met Met Ser Asn Asn Lys Arg

100 105 110

Val Ala Tyr Ala Arg Val Pro Ser Lys Asp Leu Leu Phe Ser Ile Val

115 120 125

Glu Glu Glu Thr Gly Lys Asp Cys Ala Lys Val Lys Thr Leu Phe Leu

130 135 140

Lys Leu Pro Gly Lys Arg Gly Phe Gly Ser Ala Gly Trp Thr Val Gln

145 150 155 160

Ala Lys Val Glu Leu Tyr Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys

165 170 175

Glu Phe Leu Cys Gly Leu Pro Cys Gly Phe Gln Glu Val Lys Ala Ala

180 185 190

Gln Gly Leu Gly Leu His Ala Phe Pro Pro Val Ser Leu Val Tyr Thr

195 200 205

Lys Lys Gln Ala Phe Gln Leu Arg Ala His Met Tyr Gln Ala Arg Ser

210 215 220

Leu Phe Ala Ala Asp Ser Ser Gly Leu Ser Asp Pro Phe Ala Arg Val

225 230 235 240

Phe Phe Ile Asn Gln Ser Gln Cys Thr Glu Val Leu Asn Glu Thr Leu

245 250 255

Cys Pro Thr Trp Asp Gln Met Leu Val Phe Asp Asn Leu Glu Leu Tyr

260 265 270

Gly Glu Ala His Glu Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu

275 280 285

Ile Tyr Asp Gln Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr

290 295 300

Phe Ala Lys Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro

305 310 315 320

Arg Phe Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala

325 330 335

Thr Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro

340 345 350

Ala Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Val Asp

355 360 365

Arg Gly Pro Ile Met Pro Val Pro Met Gly Ile Arg Pro Val Leu Ser

370 375 380

Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp Leu Lys Arg

385 390 395 400

Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp Ile Glu Cys Ala

405 410 415

Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn Tyr Lys Lys Asn Pro

420 425 430

Asn Phe Asn Thr Leu Val Lys Trp Phe Glu Val Asp Leu Pro Glu Asn

435 440 445

Glu Leu Leu His Pro Pro Leu Asn Ile Arg Val Val Asp Cys Arg Ala

450 455 460

Phe Gly Arg Tyr Thr Leu Val Gly Ser His Ala Val Ser Ser Leu Arg

465 470 475 480

Arg Phe Ile Tyr Arg Pro Pro Asp Arg Ser Ala Pro Ser Trp Asn Thr

485 490 495

Thr Gly Glu Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys Lys

500 505 510

Leu Glu Thr Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val Val Lys

515 520 525

Val Asp Val Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys Lys Lys Gly

530 535 540

Thr Ala Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp

545 550 555 560

Trp Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu

565 570 575

Arg Gln Gln Glu Pro Ser Gly Ile Asp Leu Glu Glu Lys Glu Glu Val

580 585 590

Asp Asn Thr Glu Gly Leu Lys Gly Ser Met Lys Gly Lys Glu Lys Ala

595 600 605

Arg Ala Ala Lys Glu Glu Lys Lys Lys Lys Thr Gln Ser Ser Gly Ser

610 615 620

Gly Gln Gly Ser Glu Ala Pro Glu Lys Lys Lys Pro Lys Ile Asp Glu

625 630 635 640

Leu Lys Val Tyr Pro Lys Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu

645 650 655

Asp Trp Leu His Thr Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp

660 665 670

Glu Asp Gly Ser Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly

675 680 685

Ser Leu Cys Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu

690 695 700

Ala Gly Tyr Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn

705 710 715 720

Asp Pro Ile Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp

725 730 735

Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile

740 745 750

Arg Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys

755 760 765

Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe

770 775 780

Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val

785 790 795 800

Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg

805 810 815

Phe Tyr Ser Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr Ser

820 825 830

Thr His Gly Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser Gln Ile

835 840 845

Leu Thr Arg Leu Cys Lys Asp Gly Lys Val Asp Gly Pro His Phe Gly

850 855 860

Pro Pro Gly Arg Val Lys Val Ala Asn Arg Val Phe Thr Gly Pro Ser

865 870 875 880

Glu Ile Glu Asp Glu Asn Gly Gln Arg Lys Pro Thr Asp Glu His Val

885 890 895

Ala Leu Leu Ala Leu Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys

900 905 910

Arg Leu Val Pro Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp

915 920 925

Lys Pro Gly Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe

930 935 940

Pro Met Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg

945 950 955 960

Lys Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu

965 970 975

Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser Asp

980 985 990

Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys Gln Asp

995 1000 1005

Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn Phe Asn

1010 1015 1020

Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu Glu Lys

1025 1030 1035

Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp Glu Thr

1040 1045 1050

Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp Asp Ala

1055 1060 1065

Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu Leu Asp

1070 1075 1080

Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln Cys Thr

1085 1090 1095

Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val Ser Ile

1100 1105 1110

Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu Ala Arg

1115 1120 1125

Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu Ala Glu

1130 1135 1140

Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro Val Gly

1145 1150 1155

Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn Arg Pro

1160 1165 1170

Asp Thr Ala Phe Val Trp Phe Leu Asn Pro Leu Lys Ser Ile Lys

1175 1180 1185

Tyr Leu Ile Cys Thr Arg Tyr Lys Trp Leu Ile Ile Lys Ile Val

1190 1195 1200

Leu Ala Leu Leu Gly Leu Leu Met Leu Gly Leu Phe Leu Tyr Ser

1205 1210 1215

Leu Pro Gly Tyr Met Val Lys Lys Leu Leu Gly Ala

1220 1225 1230

<210> 10

<211> 3693

<212> DNA

<213> 智人（Homo sapiens）

<400> 10

atgatcaaaa cggagaagtc ctaccctgag cgtcgcctgc ggggcgtcct ggaggagctg 60

agctgtggct gctgccgctt cctctccctc gctgacaagg accagggcca ctcatcccgc 120

accaggcttg accgggagcg cctcaagtcc tgcatgaggg agctggaaaa catggggcag 180

caggccagga tgctgcgggc ccaggtgaag cggcacacgg tgcgggacaa gctgaggctg 240

tgccagaact tcctgcagaa gctgcgcttc ctggcggacg agccccagca cagcattccc 300

gacatcttca tctggatgat gagcaacaac aagcgtgtcg cctatgcccg tgtgccctcc 360

aaggacctgc tcttctccat cgtggaggag gagactggca aggactgcgc caaggtcaag 420

acgctcttcc ttaagctgcc agggaagcgg ggcttcggct cggcaggctg gacagtgcag 480

gccaaggtgg agctgtacct gtggctgggc ctcagcaaac agcgcaagga gttcctgtgc 540

ggcctgccct gtggcttcca ggaggtcaag gcagcccagg gcctgggcct gcatgccttc 600

ccacccgtca gcctggtcta caccaagaag caggcgttcc agctccgagc gcacatgtac 660

caggcccgca gcctctttgc cgccgacagc agcggactct cagacccctt tgcccgcgtc 720

ttcttcatca atcagagtca gtgcacagag gtgctgaatg agaccctgtg tcccacctgg 780

gaccagatgc tggtgttcga caacctggag ctctatggtg aagctcatga gctgagggac 840

gatccgccca tcattgtcat tgaaatctat gaccaggatt ccatgggcaa agctgacttc 900

atgggccgga ccttcgccaa acccctggtg aagatggcag acgaggcgta ctgcccaccc 960

cgcttcccac ctcagctcga gtactaccag atctaccgtg gcaacgccac agctggagac 1020

ctgctggcgg ccttcgagct gctgcagatt ggaccagcag ggaaggctga cctgcccccc 1080

atcaatggcc cggtggacgt ggaccgaggt cccatcatgc ccgtgcccat gggcatccgg 1140

cccgtgctca gcaagtaccg agtggaggtg ctgttctggg gcctacggga cctaaagcgg 1200

gtgaacctgg cccaggtgga ccggccacgg gtggacatcg agtgtgcagg gaagggggtg 1260

cagtcgtccc tgatccacaa ttataagaag aaccccaact tcaacaccct cgtcaagtgg 1320

tttgaagtgg acctcccaga gaacgagctg ctgcacccgc ccttgaacat ccgtgtggtg 1380

gactgccggg ccttcggtcg ctacacactg gtgggctccc atgccgtcag ctccctgcga 1440

cgcttcatct accggccccc agaccgctcg gcccccagct ggaacaccac gggggaggtt 1500

gtggtgacta tggagccaga ggtacccatc aagaaactgg agaccatggt gaagctggac 1560

gcgacttctg aagctgttgt caaggtggat gtggctgagg aggagaagga gaagaagaag 1620

aagaagaagg gcactgcgga ggagccagag gaggaggagc cagacgagag catgctggac 1680

tggtggtcca agtactttgc ctccattgac accatgaagg agcaacttcg acaacaagag 1740

ccctctggaa ttgacttgga ggagaaggag gaagtggaca ataccgaggg cctgaagggg 1800

tcaatgaagg gcaaggagaa ggcaagggct gccaaagagg agaagaagaa gaaaactcag 1860

agctctggct ctggccaggg gtccgaggcc cccgagaaga agaaacccaa gattgatgag 1920

cttaaggtat accccaaaga gctggagtcc gagtttgata actttgagga ctggctgcac 1980

actttcaact tgcttcgggg caagaccggg gatgatgagg atggctccac cgaggaggag 2040

cgcattgtgg gacgcttcaa gggctccctc tgcgtgtaca aagtgccact cccagaggac 2100

gtgtcccggg aagccggcta cgactccacc tacggcatgt tccagggcat cccgagcaat 2160

gaccccatca atgtgctggt ccgagtctat gtggtccggg ccacggacct gcaccctgct 2220

gacatcaacg gcaaagctga cccctacatc gccatccggc taggcaagac tgacatccgc 2280

gacaaggaga actacatctc caagcagctc aaccctgtct ttgggaagtc ctttgacatc 2340

gaggcctcct tccccatgga atccatgctg acggtggctg tgtatgactg ggacctggtg 2400

ggcactgatg acctcattgg ggaaaccaag atcgacctgg agaaccgctt ctacagcaag 2460

caccgcgcca cctgcggcat cgcccagacc tactccacac atggctacaa tatctggcgg 2520

gaccccatga agcccagcca gatcctgacc cgcctctgca aagacggcaa agtggacggc 2580

ccccactttg ggccccctgg gagagtgaag gtggccaacc gcgtcttcac tgggccctct 2640

gagattgagg acgagaacgg tcagaggaag cccacagacg agcatgtggc gctgttggcc 2700

ctgaggcact gggaggacat cccccgcgca ggctgccgcc tggtgccaga gcatgtggag 2760

acgaggccgc tgctcaaccc cgacaagccg ggcatcgagc agggccgcct ggagctgtgg 2820

gtggacatgt tccccatgga catgccagcc cctgggacgc ctctggacat ctcacctcgg 2880

aagcccaaga agtacgagct gcgggtcatc atctggaaca cagatgaggt ggtcttggag 2940

gacgacgact tcttcacagg ggagaagtcc agtgacatct tcgtgagggg gtggctgaag 3000

ggccagcagg aggacaagca ggacacagac gtccactacc actccctcac tggcgagggc 3060

aacttcaact ggcgctacct gttccccttc gactacctgg cggcggagga gaagatcgtc 3120

atctccaaga aggagtccat gttctcctgg gacgagaccg agtacaagat ccccgcgcgg 3180

ctcaccctgc agatctggga tgcggaccac ttctccgctg acgacttcct gggggccatc 3240

gagctggacc tgaaccggtt cccgcggggc gcaaagacag ccaagcagtg caccatggag 3300

atggccaccg gggaggtgga cgtgcccctc gtgtccatct tcaagcaaaa gcgcgtcaaa 3360

ggctggtggc ccctcctggc ccgcaatgag aacgatgagt ttgagctcac gggcaaggtg 3420

gaggctgagc tgcatttact gacagcagag gaggcagaga agaacccagt gggcctggcc 3480

cgcaatgaac ctgaccccct agagaaaccc aaccggcccg acacggcctt cgtctggttc 3540

ctcaaccctc tcaagtccat caagtacctc atctgcaccc ggtacaagtg gctcatcatc 3600

aagatcgtgc tggcgctgtt ggggctgctc atgttggggc tcttcctcta cagcctccct 3660

ggctacatgg tcaaaaagct ccttggggca tga 3693

<210> 11

<211> 1992

<212> PRT

<213> 小家鼠（Mus musculus）

<400> 11

Met Ala Leu Ile Val His Leu Lys Thr Val Ser Glu Leu Arg Gly Lys

1 5 10 15

Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser

20 25 30

Arg Val Leu Glu Asn Cys Glu Gly Val Ala Asp Phe Asp Glu Thr Phe

35 40 45

Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Val Leu Glu Ile

50 55 60

Gln Ile Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr

65 70 75 80

Phe Cys Met Val Leu Gln Lys Val Val Glu Glu Asn Arg Val Glu Val

85 90 95

Thr Asp Thr Leu Met Asp Asp Ser Asn Ala Ile Ile Lys Thr Ser Leu

100 105 110

Ser Met Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Pro Trp

115 120 125

Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Lys Asp

130 135 140

Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Thr Arg

145 150 155 160

Ile Ser Gly Glu Lys Ser Phe Arg Ser Lys Gly Arg Glu Glu Thr Lys

165 170 175

Gly Gly Arg Asp Gly Glu His Lys Ala Gly Arg Ser Val Phe Ser Ala

180 185 190

Met Lys Leu Gly Lys Thr Arg Ser His Lys Glu Glu Pro Gln Arg Gln

195 200 205

Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu Ala Ile

210 215 220

Gln Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala Ser Val

225 230 235 240

Thr Ala Leu Thr Ser Asn Val Ser Asn Lys Arg Ser Lys Pro Asp Ile

245 250 255

Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val Ser Ile

260 265 270

Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp Pro Val

275 280 285

Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met Lys Glu

290 295 300

Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp Phe His

305 310 315 320

Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser Val Ile

325 330 335

His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser Phe Lys

340 345 350

Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe His His

355 360 365

Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ala Gly Leu Lys

370 375 380

Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp Asn Ile

385 390 395 400

Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile Glu Gly

405 410 415

Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp Ala Arg

420 425 430

Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met Asn Thr

435 440 445

Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn Lys Asp

450 455 460

Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys Gly Lys

465 470 475 480

Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu Gln Val

485 490 495

Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys Val Gln

500 505 510

Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr His Phe

515 520 525

Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe Leu Pro

530 535 540

Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg Asn Tyr

545 550 555 560

Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly Glu Gly

565 570 575

Val Ser Phe Arg Ala Arg Leu Met Leu Gly Leu Ala Val Glu Ile Leu

580 585 590

Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln Val Glu

595 600 605

Gln Ala Thr Pro Val Ser Glu Ser Cys Thr Gly Arg Met Glu Glu Phe

610 615 620

Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg Lys Asn

625 630 635 640

Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr Gly Asn

645 650 655

Glu Val Asp Gly Met Ser Arg Pro Leu Arg Pro Arg Pro Arg Lys Glu

660 665 670

Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ser Ser Asp Asp

675 680 685

Glu Gly Asp Glu Ala Gly Asp Leu Ala Ser Val Ser Ser Thr Pro Pro

690 695 700

Met Arg Pro Gln Ile Thr Asp Arg Asn Tyr Phe His Leu Pro Tyr Leu

705 710 715 720

Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp Gln Arg

725 730 735

Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp Lys Leu

740 745 750

Glu Glu Gly Leu Asn Asp Val Gln Glu Met Ile Lys Thr Glu Lys Ser

755 760 765

Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser Cys Gly

770 775 780

Cys His Arg Phe Leu Ser Leu Ser Asp Lys Asp Gln Gly Arg Ser Ser

785 790 795 800

Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg Glu Leu

805 810 815

Glu Ser Met Gly Gln Gln Ala Lys Ser Leu Arg Ala Gln Val Lys Arg

820 825 830

His Thr Val Arg Asp Lys Leu Arg Leu Cys Gln Asn Phe Leu Gln Lys

835 840 845

Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp Val Phe

850 855 860

Ile Trp Met Met Ser Asn Asn Lys Arg Ile Ala Tyr Ala Arg Val Pro

865 870 875 880

Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Leu Gly Lys Asp

885 890 895

Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys Arg Gly

900 905 910

Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Leu Glu Leu Tyr Leu

915 920 925

Trp Leu Gly Leu Ser Lys Gln Arg Lys Asp Phe Leu Cys Gly Leu Pro

930 935 940

Cys Gly Phe Glu Glu Val Lys Ala Ala Gln Gly Leu Gly Leu His Ser

945 950 955 960

Phe Pro Pro Ile Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe Gln Leu

965 970 975

Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp Ser Ser

980 985 990

Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln Ser Gln

995 1000 1005

Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp Gln

1010 1015 1020

Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His Glu

1025 1030 1035

Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp Gln

1040 1045 1050

Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala Lys

1055 1060 1065

Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg Phe

1070 1075 1080

Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Ser Ala Thr

1085 1090 1095

Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro

1100 1105 1110

Ser Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Met

1115 1120 1125

Asp Arg Gly Pro Ile Met Pro Val Pro Val Gly Ile Arg Pro Val

1130 1135 1140

Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp

1145 1150 1155

Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp

1160 1165 1170

Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn

1175 1180 1185

Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe Glu

1190 1195 1200

Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn Ile

1205 1210 1215

Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val Gly

1220 1225 1230

Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro Pro

1235 1240 1245

Asp Arg Ser Ala Pro Asn Trp Asn Thr Thr Gly Glu Val Val Val

1250 1255 1260

Ser Met Glu Pro Glu Glu Pro Val Lys Lys Leu Glu Thr Met Val

1265 1270 1275

Lys Leu Asp Ala Thr Ser Asp Ala Val Val Lys Val Asp Val Ala

1280 1285 1290

Glu Asp Glu Lys Glu Arg Lys Lys Lys Lys Lys Lys Gly Pro Ser

1295 1300 1305

Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp Trp

1310 1315 1320

Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu

1325 1330 1335

Arg Gln His Glu Thr Ser Gly Thr Asp Leu Glu Glu Lys Glu Glu

1340 1345 1350

Met Glu Ser Ala Glu Gly Leu Lys Gly Pro Met Lys Ser Lys Glu

1355 1360 1365

Lys Ser Arg Ala Ala Lys Glu Glu Lys Lys Lys Lys Asn Gln Ser

1370 1375 1380

Pro Gly Pro Gly Gln Gly Ser Glu Ala Pro Glu Lys Lys Lys Ala

1385 1390 1395

Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys Glu Leu Glu Ser Glu

1400 1405 1410

Phe Asp Ser Phe Glu Asp Trp Leu His Thr Phe Asn Leu Leu Arg

1415 1420 1425

Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser Thr Glu Glu Glu Arg

1430 1435 1440

Ile Val Gly Arg Phe Lys Gly Ser Leu Cys Val Tyr Lys Val Pro

1445 1450 1455

Leu Pro Glu Asp Val Ser Arg Glu Ala Gly Tyr Asp Pro Thr Tyr

1460 1465 1470

Gly Met Phe Gln Gly Ile Pro Ser Asn Asp Pro Ile Asn Val Leu

1475 1480 1485

Val Arg Ile Tyr Val Val Arg Ala Thr Asp Leu His Pro Ala Asp

1490 1495 1500

Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile Lys Leu Gly Lys

1505 1510 1515

Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys Gln Leu Asn

1520 1525 1530

Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe Pro Met

1535 1540 1545

Glu Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val Gly

1550 1555 1560

Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg

1565 1570 1575

Phe Tyr Ser Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr

1580 1585 1590

Ser Ile His Gly Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser

1595 1600 1605

Gln Ile Leu Thr Arg Leu Cys Lys Glu Gly Lys Val Asp Gly Pro

1610 1615 1620

His Phe Gly Pro His Gly Arg Val Arg Val Ala Asn Arg Val Phe

1625 1630 1635

Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn Gly Gln Arg Lys Pro

1640 1645 1650

Thr Asp Glu His Val Ala Leu Ser Ala Leu Arg His Trp Glu Asp

1655 1660 1665

Ile Pro Arg Val Gly Cys Arg Leu Val Pro Glu His Val Glu Thr

1670 1675 1680

Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly Ile Glu Gln Gly Arg

1685 1690 1695

Leu Glu Leu Trp Val Asp Met Phe Pro Met Asp Met Pro Ala Pro

1700 1705 1710

Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys Pro Lys Lys Tyr Glu

1715 1720 1725

Leu Arg Val Ile Val Trp Asn Thr Asp Glu Val Val Leu Glu Asp

1730 1735 1740

Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser Asp Ile Phe Val Arg

1745 1750 1755

Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys Gln Asp Thr Asp Val

1760 1765 1770

His Tyr His Ser Leu Thr Gly Glu Gly Asn Phe Asn Trp Arg Tyr

1775 1780 1785

Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu Glu Lys Ile Val Met

1790 1795 1800

Ser Lys Lys Glu Ser Met Phe Ser Trp Asp Glu Thr Glu Tyr Lys

1805 1810 1815

Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp Asp Ala Asp His Phe

1820 1825 1830

Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu Leu Asp Leu Asn Arg

1835 1840 1845

Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln Cys Thr Met Glu Met

1850 1855 1860

Ala Thr Gly Glu Val Asp Val Pro Leu Val Ser Ile Phe Lys Gln

1865 1870 1875

Lys Arg Val Lys Gly Trp Trp Pro Leu Leu Ala Arg Asn Glu Asn

1880 1885 1890

Asp Glu Phe Glu Leu Thr Gly Lys Val Glu Ala Glu Leu His Leu

1895 1900 1905

Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro Val Gly Leu Ala Arg

1910 1915 1920

Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn Arg Pro Asp Thr Ala

1925 1930 1935

Phe Val Trp Phe Leu Asn Pro Leu Lys Ser Ile Lys Tyr Leu Ile

1940 1945 1950

Cys Thr Arg Tyr Lys Trp Leu Ile Ile Lys Ile Val Leu Ala Leu

1955 1960 1965

Leu Gly Leu Leu Met Leu Ala Leu Phe Leu Tyr Ser Leu Pro Gly

1970 1975 1980

Tyr Met Val Lys Lys Leu Leu Gly Ala

1985 1990

<210> 12

<211> 5979

<212> DNA

<213> 小家鼠（Mus musculus）

<400> 12

atggccctga ttgttcacct caagactgtc tcagagctcc gaggcaaagg tgaccggatt 60

gccaaagtca ctttccgagg gcagtctttc tactcccggg tcctggagaa ctgcgagggt 120

gtggctgact ttgatgagac gttccggtgg ccagtggcca gcagcatcga ccggaatgaa 180

gtgttggaga ttcagatttt caactacagc aaagtcttca gcaacaagct gatagggacc 240

ttctgcatgg tgctgcagaa agtggtggag gagaatcggg tagaggtgac cgacacgctg 300

atggatgaca gcaatgctat catcaagacc agcctgagca tggaggtccg gtatcaggcc 360

acagatggca ctgtgggccc ctgggatgat ggagacttcc tgggagatga atccctccag 420

gaggagaagg acagccagga gacagatggg ctgctacctg gttcccgacc cagcacccgg 480

atatctggcg agaagagctt tcgcagcaaa ggcagagaga agaccaaggg aggcagagat 540

ggcgagcaca aagcgggaag gagtgtgttc tcggccatga aactcggcaa aactcggtcc 600

cacaaagagg agccccaaag acaagatgag ccagcagtgc tggagatgga ggacctggac 660

cacctagcca ttcagctggg ggatgggctg gatcctgact ccgtgtctct agcctcggtc 720

accgctctca ccagcaatgt ctccaacaaa cggtctaagc cagatattaa gatggagccc 780

agtgctggaa ggcccatgga ttaccaggtc agcatcacag tgattgaggc tcggcagctg 840

gtgggcttga acatggaccc tgtggtgtgt gtggaggtgg gtgatgacaa gaaatacacg 900

tcaatgaagg agtccacaaa ctgcccttac tacaacgagt actttgtctt cgacttccat 960

gtctctcctg atgtcatgtt tgacaagatc atcaagatct cggttatcca ttctaagaac 1020

ctgcttcgga gcggcaccct ggtgggttcc ttcaaaatgg atgtggggac tgtgtattcc 1080

cagcctgaac accagttcca tcacaaatgg gccatcctgt cagaccccga tgacatctct 1140

gctgggttga agggttatgt aaagtgtgat gtcgctgtgg tgggcaaggg agacaacatc 1200

aagacacccc acaaggccaa cgagacggat gaggacgaca ttgaagggaa cttgctgctc 1260

cccgagggcg tgccccccga acggcagtgg gcacggttct atgtgaaaat ttaccgagca 1320

gagggactgc cccggatgaa cacaagcctc atggccaacg tgaagaaggc gttcatcggt 1380

gagaacaagg acctcgtcga cccctatgtg caagtcttct ttgctggaca aaagggcaaa 1440

acatcagtgc agaagagcag ctatgagccg ctatggaatg agcaggtcgt cttcacagac 1500

ttgttccccc cactctgcaa acgcatgaag gtgcagatcc gggactctga caaggtcaat 1560

gatgtggcca tcggcaccca cttcatcgac ctgcgcaaga tttccaacga tggagacaaa 1620

ggcttcctgc ctaccctcgg tccagcctgg gtgaacatgt acggctccac gcgcaactac 1680

acactgctgg acgagcacca ggacttgaat gaaggcctgg gggagggtgt gtccttccgg 1740

gcccgcctca tgttgggact agctgtggag atcctggaca cctccaaccc agagctcacc 1800

agctccacgg aggtgcaggt ggagcaggcc acgcctgtct cggagagctg cacagggaga 1860

atggaagaat tttttctatt tggagccttc ttggaagcct caatgattga ccggaaaaat 1920

ggggacaagc caattacctt tgaggtgacc ataggaaact acggcaatga agtcgatggt 1980

atgtcccggc ccctgaggcc tcggccccgg aaagagcctg gggatgaaga agaggtagac 2040

ctgattcaga actccagtga cgatgaaggt gacgaagccg gggacctggc ctcggtgtcc 2100

tccaccccac ctatgcggcc ccagatcacg gacaggaact atttccacct gccctacctg 2160

gagcgcaagc cctgcatcta tatcaagagc tggtggcctg accagaggcg gcgcctctac 2220

aatgccaaca tcatggatca cattgctgac aagctggaag aaggcctgaa tgatgtacag 2280

gagatgatca aaacggagaa gtcctacccg gagcgccgcc tgcggggtgt gctagaggaa 2340

ctcagctgtg gctgccaccg cttcctctcc ctctcggaca aggaccaggg ccgctcgtcc 2400

cgcaccaggc tggatcgaga gcgtcttaag tcctgtatga gggagttgga gagcatggga 2460

cagcaggcca agagcctgag ggctcaggtg aagcggcaca ctgttcggga caagctgagg 2520

tcatgccaga actttctgca gaagctacgc ttcctggcgg atgagcccca gcacagcatt 2580

cctgatgtgt tcatttggat gatgagcaac aacaaacgta tcgcctatgc ccgcgtgcct 2640

tccaaagacc tgctcttctc catcgtggag gaggaactgg gcaaggactg cgccaaagtc 2700

aagaccctct tcctgaagct gccagggaag aggggcttcg gctcggcagg ctggacagta 2760

caggccaagc tggagctcta cctgtggctg ggcctcagca agcagcgaaa ggacttcctg 2820

tgtggtctgc cctgtggctt cgaggaggtc aaggcagccc aaggcctggg cctgcattcc 2880

tttccgccca tcagcctagt ctacaccaag aagcaagcct tccagctccg agcacacatg 2940

tatcaggccc gaagcctctt tgctgctgac agcagtgggc tctctgatcc ctttgcccgt 3000

gtcttcttca tcaaccagag ccaatgcact gaggttctaa acgagacact gtgtcccacc 3060

tgggaccaga tgctggtatt tgacaacctg gagctgtacg gtgaagctca cgagttacga 3120

gatgatcccc ccatcattgt cattgaaatc tacgaccagg acagcatggg caaagccgac 3180

ttcatgggcc ggaccttcgc caagcccctg gtgaagatgg cagatgaagc atactgccca 3240

cctcgcttcc cgccgcagct tgagtactac cagatctacc gaggcagtgc cactgccgga 3300

gacctactgg ctgccttcga gctgctgcag attgggccat cagggaaggc tgacctgcca 3360

cccatcaatg gcccagtgga catggacaga gggcccatca tgcctgtgcc cgtgggaatc 3420

cggccagtgc tcagcaagta ccgagtggag gtgctgttct ggggcctgag ggacctaaag 3480

agggtgaacc tggcccaggt ggaccgacca cgggtggaca tcgagtgtgc aggaaagggg 3540

gtacaatcct ccctgattca caattataag aagaacccca acttcaacac gctggtcaag 3600

tggtttgaag tggacctccc ggagaatgag ctcctgcacc cacccttgaa catccgagtg 3660

gtagattgcc gggcctttgg acgatacacc ctggtgggtt cccacgcagt cagctcactg 3720

aggcgcttca tctaccgacc tccagaccgc tcagccccca actggaacac cacaggggag 3780

gttgtagtaa gcatggagcc tgaggagcca gttaagaagc tggagaccat ggtgaaactg 3840

gatgcgactt ctgatgctgt ggtcaaggtg gatgtggctg aagatgagaa ggaaaggaag 3900

aagaagaaaa agaaaggccc gtcagaggag ccagaggagg aagagcccga tgagagcatg 3960

ctggattggt ggtccaagta cttcgcctcc atcgacacaa tgaaggagca acttcgacaa 4020

catgagacct ctggaactga cttggaagag aaggaagaga tggaaagcgc tgagggcctg 4080

aagggaccaa tgaagagcaa ggagaagtcc agagctgcaa aggaggagaa aaagaagaaa 4140

aaccagagcc ctggccctgg ccagggatcg gaggctcctg agaagaagaa agccaagatc 4200

gatgagctta aggtgtaccc caaggagctg gaatcggagt ttgacagctt tgaggactgg 4260

ctgcacacct tcaacctgtt gaggggcaag acgggagatg atgaggatgg ctccacagag 4320

gaggagcgca tagtaggccg attcaagggc tccctctgtg tgtacaaagt gccactccca 4380

gaagatgtat ctcgagaagc tggctatgat cccacctatg gaatgttcca gggcatccca 4440

agcaatgacc ccatcaatgt gctggtccga atctatgtgg tccgggccac agacctgcac 4500

ccggccgaca tcaatggcaa agctgacccc tatattgcca tcaagttagg caagaccgac 4560

atccgagaca aggagaacta catctccaag cagctcaacc ctgtgtttgg gaagtccttt 4620

gacattgagg cctccttccc catggagtcc atgttgacag tggccgtgta cgactgggat 4680

ctggtgggca ctgatgacct catcggagaa accaagattg acctggaaaa ccgcttctac 4740

agcaagcatc gcgccacctg cggcatcgca cagacctatt ccatacatgg ctacaatatc 4800

tggagggacc ccatgaagcc cagccagatc ctgacacgcc tctgtaaaga gggcaaagtg 4860

gacggccccc actttggtcc ccatgggaga gtgagggttg ccaaccgtgt cttcacgggg 4920

ccttcagaaa tagaggatga gaatggtcag aggaagccca cagatgagca cgtggcactg 4980

tctgctctga gacactggga ggacatcccc cgggtgggct gccgccttgt gccggaacac 5040

gtggagacca ggccgctgct caaccctgac aagccaggca ttgagcaggg ccgcctggag 5100

ctgtgggtgg acatgttccc catggacatg ccagcccctg ggacacctct ggatatatcc 5160

cccaggaaac ccaagaagta cgagctgcgg gtcatcgtgt ggaacacaga cgaggtggtc 5220

ctggaagacg atgatttctt cacgggagag aagtccagtg acatttttgt gagggggtgg 5280

ctgaagggcc agcaggagga caaacaggac acagatgtcc actatcactc cctcacgggg 5340

gagggcaact tcaactggag atacctcttc cccttcgact acctagcggc cgaagagaag 5400

atcgttatgt ccaaaaagga gtctatgttc tcctgggatg agacggagta caagatccct 5460

gcgcggctca ccctgcagat ctgggacgct gaccacttct cggctgacga cttcctgggg 5520

gctatcgagc tggacctgaa ccggttcccg aggggcgcta agacagccaa gcagtgcacc 5580

atggagatgg ccaccgggga ggtggacgta cccctggttt ccatctttaa acagaaacgt 5640

gtcaaaggct ggtggcccct cctggcccgc aatgagaatg atgagtttga gctcacaggc 5700

aaagtggagg cggagctaca cctactcacg gcagaggagg cagagaagaa ccctgtgggc 5760

ctggctcgca atgaacctga tcccctagaa aaacccaacc ggcctgacac ggcattcgtc 5820

tggttcctga acccactcaa atctatcaag tacctcatct gcacccggta caagtggctg 5880

atcatcaaga tcgtgctggc gctgctgggg ctgctcatgc tggccctctt cctttacagc 5940

ctcccaggct acatggtcaa gaagctccta ggggcctga 5979

<210> 13

<211> 1977

<212> PRT

<213> 小家鼠（Mus musculus）

<400> 13

Met Ala Leu Ile Val His Leu Lys Thr Val Ser Glu Leu Arg Gly Lys

1 5 10 15

Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser

20 25 30

Arg Val Leu Glu Asn Cys Glu Gly Val Ala Asp Phe Asp Glu Thr Phe

35 40 45

Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Val Leu Glu Ile

50 55 60

Gln Ile Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr

65 70 75 80

Phe Cys Met Val Leu Gln Lys Val Val Glu Glu Asn Arg Val Glu Val

85 90 95

Thr Asp Thr Leu Met Asp Asp Ser Asn Ala Ile Ile Lys Thr Ser Leu

100 105 110

Ser Met Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Pro Trp

115 120 125

Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Lys Asp

130 135 140

Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Thr Arg

145 150 155 160

Ile Ser Gly Glu Lys Ser Phe Arg Arg Ala Gly Arg Ser Val Phe Ser

165 170 175

Ala Met Lys Leu Gly Lys Thr Arg Ser His Lys Glu Glu Pro Gln Arg

180 185 190

Gln Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu Ala

195 200 205

Ile Gln Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala Ser

210 215 220

Val Thr Ala Leu Thr Ser Asn Val Ser Asn Lys Arg Ser Lys Pro Asp

225 230 235 240

Ile Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val Ser

245 250 255

Ile Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp Pro

260 265 270

Val Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met Lys

275 280 285

Glu Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp Phe

290 295 300

His Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser Val

305 310 315 320

Ile His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser Phe

325 330 335

Lys Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe His

340 345 350

His Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ala Gly Leu

355 360 365

Lys Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp Asn

370 375 380

Ile Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile Glu

385 390 395 400

Gly Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp Ala

405 410 415

Arg Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met Asn

420 425 430

Thr Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn Lys

435 440 445

Asp Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys Gly

450 455 460

Lys Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu Gln

465 470 475 480

Val Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys Val

485 490 495

Gln Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr His

500 505 510

Phe Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe Leu

515 520 525

Pro Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg Asn

530 535 540

Tyr Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly Glu

545 550 555 560

Gly Val Ser Phe Arg Ala Arg Leu Met Leu Gly Leu Ala Val Glu Ile

565 570 575

Leu Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln Val

580 585 590

Glu Gln Ala Thr Pro Val Ser Glu Ser Cys Thr Gly Arg Met Glu Glu

595 600 605

Phe Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg Lys

610 615 620

Asn Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr Gly

625 630 635 640

Asn Glu Val Asp Gly Met Ser Arg Pro Leu Arg Pro Arg Pro Arg Lys

645 650 655

Glu Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ser Ser Asp

660 665 670

Asp Glu Gly Asp Glu Ala Gly Asp Leu Ala Ser Val Ser Ser Thr Pro

675 680 685

Pro Met Arg Pro Gln Ile Thr Asp Arg Asn Tyr Phe His Leu Pro Tyr

690 695 700

Leu Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp Gln

705 710 715 720

Arg Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp Lys

725 730 735

Leu Glu Glu Gly Leu Asn Asp Val Gln Glu Met Ile Lys Thr Glu Lys

740 745 750

Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser Cys

755 760 765

Gly Cys His Arg Phe Leu Ser Leu Ser Asp Lys Asp Gln Gly Arg Ser

770 775 780

Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg Glu

785 790 795 800

Leu Glu Ser Met Gly Gln Gln Ala Lys Ser Leu Arg Ala Gln Val Lys

805 810 815

Arg His Thr Val Arg Asp Lys Leu Arg Ser Cys Gln Asn Phe Leu Gln

820 825 830

Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp Val

835 840 845

Phe Ile Trp Met Met Ser Asn Asn Lys Arg Ile Ala Tyr Ala Arg Val

850 855 860

Pro Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Leu Gly Lys

865 870 875 880

Asp Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys Arg

885 890 895

Gly Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Leu Glu Leu Tyr

900 905 910

Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys Asp Phe Leu Cys Gly Leu

915 920 925

Pro Cys Gly Phe Glu Glu Val Lys Ala Ala Gln Gly Leu Gly Leu His

930 935 940

Ser Phe Pro Pro Ile Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe Gln

945 950 955 960

Leu Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp Ser

965 970 975

Ser Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln Ser

980 985 990

Gln Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp Gln

995 1000 1005

Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His Glu

1010 1015 1020

Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp Gln

1025 1030 1035

Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala Lys

1040 1045 1050

Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg Phe

1055 1060 1065

Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Ser Ala Thr

1070 1075 1080

Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro

1085 1090 1095

Ser Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Met

1100 1105 1110

Asp Arg Gly Pro Ile Met Pro Val Pro Val Gly Ile Arg Pro Val

1115 1120 1125

Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp

1130 1135 1140

Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp

1145 1150 1155

Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn

1160 1165 1170

Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe Glu

1175 1180 1185

Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn Ile

1190 1195 1200

Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val Gly

1205 1210 1215

Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro Pro

1220 1225 1230

Asp Arg Ser Ala Pro Asn Trp Asn Thr Thr Gly Glu Val Val Val

1235 1240 1245

Ser Met Glu Pro Glu Glu Pro Val Lys Lys Leu Glu Thr Met Val

1250 1255 1260

Lys Leu Asp Ala Thr Ser Asp Ala Val Val Lys Val Asp Val Ala

1265 1270 1275

Glu Asp Glu Lys Glu Arg Lys Lys Lys Lys Lys Lys Gly Pro Ser

1280 1285 1290

Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp Trp

1295 1300 1305

Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu

1310 1315 1320

Arg Gln His Glu Thr Ser Gly Thr Asp Leu Glu Glu Lys Glu Glu

1325 1330 1335

Met Glu Ser Ala Glu Gly Leu Lys Gly Pro Met Lys Ser Lys Glu

1340 1345 1350

Lys Ser Arg Ala Ala Lys Glu Glu Lys Lys Lys Lys Asn Gln Ser

1355 1360 1365

Pro Gly Pro Gly Gln Gly Ser Glu Ala Pro Glu Lys Lys Lys Ala

1370 1375 1380

Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys Glu Leu Glu Ser Glu

1385 1390 1395

Phe Asp Ser Phe Glu Asp Trp Leu His Thr Phe Asn Leu Leu Arg

1400 1405 1410

Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser Thr Glu Glu Glu Arg

1415 1420 1425

Ile Val Gly Arg Phe Lys Gly Ser Leu Cys Val Tyr Lys Val Pro

1430 1435 1440

Leu Pro Glu Asp Val Ser Arg Glu Ala Gly Tyr Asp Pro Thr Tyr

1445 1450 1455

Gly Met Phe Gln Gly Ile Pro Ser Asn Asp Pro Ile Asn Val Leu

1460 1465 1470

Val Arg Ile Tyr Val Val Arg Ala Thr Asp Leu His Pro Ala Asp

1475 1480 1485

Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile Lys Leu Gly Lys

1490 1495 1500

Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys Gln Leu Asn

1505 1510 1515

Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe Pro Met

1520 1525 1530

Glu Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val Gly

1535 1540 1545

Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg

1550 1555 1560

Phe Tyr Ser Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr

1565 1570 1575

Ser Ile His Gly Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser

1580 1585 1590

Gln Ile Leu Thr Arg Leu Cys Lys Glu Gly Lys Val Asp Gly Pro

1595 1600 1605

His Phe Gly Pro His Gly Arg Val Arg Val Ala Asn Arg Val Phe

1610 1615 1620

Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn Gly Gln Arg Lys Pro

1625 1630 1635

Thr Asp Glu His Val Ala Leu Ser Ala Leu Arg His Trp Glu Asp

1640 1645 1650

Ile Pro Arg Val Gly Cys Arg Leu Val Pro Glu His Val Glu Thr

1655 1660 1665

Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly Ile Glu Gln Gly Arg

1670 1675 1680

Leu Glu Leu Trp Val Asp Met Phe Pro Met Asp Met Pro Ala Pro

1685 1690 1695

Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys Pro Lys Lys Tyr Glu

1700 1705 1710

Leu Arg Val Ile Val Trp Asn Thr Asp Glu Val Val Leu Glu Asp

1715 1720 1725

Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser Asp Ile Phe Val Arg

1730 1735 1740

Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys Gln Asp Thr Asp Val

1745 1750 1755

His Tyr His Ser Leu Thr Gly Glu Gly Asn Phe Asn Trp Arg Tyr

1760 1765 1770

Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu Glu Lys Ile Val Met

1775 1780 1785

Ser Lys Lys Glu Ser Met Phe Ser Trp Asp Glu Thr Glu Tyr Lys

1790 1795 1800

Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp Asp Ala Asp His Phe

1805 1810 1815

Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu Leu Asp Leu Asn Arg

1820 1825 1830

Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln Cys Thr Met Glu Met

1835 1840 1845

Ala Thr Gly Glu Val Asp Val Pro Leu Val Ser Ile Phe Lys Gln

1850 1855 1860

Lys Arg Val Lys Gly Trp Trp Pro Leu Leu Ala Arg Asn Glu Asn

1865 1870 1875

Asp Glu Phe Glu Leu Thr Gly Lys Val Glu Ala Glu Leu His Leu

1880 1885 1890

Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro Val Gly Leu Ala Arg

1895 1900 1905

Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn Arg Pro Asp Thr Ser

1910 1915 1920

Phe Ile Trp Phe Leu Asn Pro Leu Lys Ser Ala Arg Tyr Phe Leu

1925 1930 1935

Trp His Thr Tyr Arg Trp Leu Leu Leu Lys Phe Leu Leu Leu Phe

1940 1945 1950

Leu Leu Leu Leu Leu Phe Ala Leu Phe Leu Tyr Ser Leu Pro Gly

1955 1960 1965

Tyr Leu Ala Lys Lys Ile Leu Gly Ala

1970 1975

<210> 14

<211> 5934

<212> DNA

<213> 小家鼠（Mus musculus）

<400> 14

atggccctga ttgttcacct caagactgtc tcagagctcc gaggcaaagg tgaccggatt 60

gccaaagtca ctttccgagg gcagtctttc tactcccggg tcctggagaa ctgcgagggt 120

gtggctgact ttgatgagac gttccggtgg ccagtggcca gcagcatcga ccggaatgaa 180

gtgttggaga ttcagatttt caactacagc aaagtcttca gcaacaagct gatagggacc 240

ttctgcatgg tgctgcagaa agtggtggag gagaatcggg tagaggtgac cgacacgctg 300

atggatgaca gcaatgctat catcaagacc agcctgagca tggaggtccg gtatcaggcc 360

acagatggca ctgtgggccc ctgggatgat ggagacttcc tgggagatga atccctccag 420

gaggagaagg acagccagga gacagatggg ctgctacctg gttcccgacc cagcacccgg 480

atatctggcg agaagagctt tcgcagagcg ggaaggagtg tgttctcggc catgaaactc 540

ggcaaaactc ggtcccacaa agaggagccc caaagacaag atgagccagc agtgctggag 600

atggaggacc tggaccacct agccattcag ctgggggatg ggctggatcc tgactccgtg 660

tctctagcct cggtcaccgc tctcaccagc aatgtctcca acaaacggtc taagccagat 720

attaagatgg agcccagtgc tggaaggccc atggattacc aggtcagcat cacagtgatt 780

gaggctcggc agctggtggg cttgaacatg gaccctgtgg tgtgtgtgga ggtgggtgat 840

gacaagaaat acacgtcaat gaaggagtcc acaaactgcc cttactacaa cgagtacttt 900

gtcttcgact tccatgtctc tcctgatgtc atgtttgaca agatcatcaa gatctcggtt 960

atccattcta agaacctgct tcggagcggc accctggtgg gttccttcaa aatggatgtg 1020

gggactgtgt attcccagcc tgaacaccag ttccatcaca aatgggccat cctgtcagac 1080

cccgatgaca tctctgctgg gttgaagggt tatgtaaagt gtgatgtcgc tgtggtgggc 1140

aagggagaca acatcaagac accccacaag gccaacgaga cggatgagga cgacattgaa 1200

gggaacttgc tgctccccga gggcgtgccc cccgaacggc agtgggcacg gttctatgtg 1260

aaaatttacc gagcagaggg actgccccgg atgaacacaa gcctcatggc caacgtgaag 1320

aaggcgttca tcggtgagaa caaggacctc gtcgacccct atgtgcaagt cttctttgct 1380

ggacaaaagg gcaaaacatc agtgcagaag agcagctatg agccgctatg gaatgagcag 1440

gtcgtcttca cagacttgtt ccccccactc tgcaaacgca tgaaggtgca gatccgggac 1500

tctgacaagg tcaatgatgt ggccatcggc acccacttca tcgacctgcg caagatttcc 1560

aacgatggag acaaaggctt cctgcctacc ctcggtccag cctgggtgaa catgtacggc 1620

tccacgcgca actacacact gctggacgag caccaggact tgaatgaagg cctgggggag 1680

ggtgtgtcct tccgggcccg cctcatgttg ggactagctg tggagatcct ggacacctcc 1740

aacccagagc tcaccagctc cacggaggtg caggtggagc aggccacgcc tgtctcggag 1800

agctgcacag ggagaatgga agaatttttt ctatttggag ccttcttgga agcctcaatg 1860

attgaccgga aaaatgggga caagccaatt acctttgagg tgaccatagg aaactacggc 1920

aatgaagtcg atggtatgtc ccggcccctg aggcctcggc cccggaaaga gcctggggat 1980

gaagaagagg tagacctgat tcagaactcc agtgacgatg aaggtgacga agccggggac 2040

ctggcctcgg tgtcctccac cccacctatg cggccccaga tcacggacag gaactatttc 2100

cacctgccct acctggagcg caagccctgc atctatatca agagctggtg gcctgaccag 2160

aggcggcgcc tctacaatgc caacatcatg gatcacattg ctgacaagct ggaagaaggc 2220

ctgaatgatg tacaggagat gatcaaaacg gagaagtcct acccggagcg ccgcctgcgg 2280

ggtgtgctag aggaactcag ctgtggctgc caccgcttcc tctccctctc ggacaaggac 2340

cagggccgct cgtcccgcac caggctggat cgagagcgtc ttaagtcctg tatgagggag 2400

ttggagagca tgggacagca ggccaagagc ctgagggctc aggtgaagcg gcacactgtt 2460

cgggacaagc tgaggtcatg ccagaacttt ctgcagaagc tacgcttcct ggcggatgag 2520

ccccagcaca gcattcctga tgtgttcatt tggatgatga gcaacaacaa acgtatcgcc 2580

tatgcccgcg tgccttccaa agacctgctc ttctccatcg tggaggagga actgggcaag 2640

gactgcgcca aagtcaagac cctcttcctg aagctgccag ggaagagggg cttcggctcg 2700

gcaggctgga cagtacaggc caagctggag ctctacctgt ggctgggcct cagcaagcag 2760

cgaaaggact tcctgtgtgg tctgccctgt ggcttcgagg aggtcaaggc agcccaaggc 2820

ctgggcctgc attcctttcc gcccatcagc ctagtctaca ccaagaagca agccttccag 2880

ctccgagcac acatgtatca ggcccgaagc ctctttgctg ctgacagcag tgggctctct 2940

gatccctttg cccgtgtctt cttcatcaac cagagccaat gcactgaggt tctaaacgag 3000

acactgtgtc ccacctggga ccagatgctg gtatttgaca acctggagct gtacggtgaa 3060

gctcacgagt tacgagatga tccccccatc attgtcattg aaatctacga ccaggacagc 3120

atgggcaaag ccgacttcat gggccggacc ttcgccaagc ccctggtgaa gatggcagat 3180

gaagcatact gcccacctcg cttcccgccg cagcttgagt actaccagat ctaccgaggc 3240

agtgccactg ccggagacct actggctgcc ttcgagctgc tgcagattgg gccatcaggg 3300

aaggctgacc tgccacccat caatggccca gtggacatgg acagagggcc catcatgcct 3360

gtgcccgtgg gaatccggcc agtgctcagc aagtaccgag tggaggtgct gttctggggc 3420

ctgagggacc taaagagggt gaacctggcc caggtggacc gaccacgggt ggacatcgag 3480

tgtgcaggaa agggggtaca atcctccctg attcacaatt ataagaagaa ccccaacttc 3540

aacacgctgg tcaagtggtt tgaagtggac ctcccggaga atgagctcct gcacccaccc 3600

ttgaacatcc gagtggtaga ttgccgggcc tttggacgat acaccctggt gggttcccac 3660

gcagtcagct cactgaggcg cttcatctac cgacctccag accgctcagc ccccaactgg 3720

aacaccacag gggaggttgt agtaagcatg gagcctgagg agccagttaa gaagctggag 3780

accatggtga aactggatgc gacttctgat gctgtggtca aggtggatgt ggctgaagat 3840

gagaaggaaa ggaagaagaa gaaaaagaaa ggcccgtcag aggagccaga ggaggaagag 3900

cccgatgaga gcatgctgga ttggtggtcc aagtacttcg cctccatcga cacaatgaag 3960

gagcaacttc gacaacatga gacctctgga actgacttgg aagagaagga agagatggaa 4020

agcgctgagg gcctgaaggg accaatgaag agcaaggaga agtccagagc tgcaaaggag 4080

gagaaaaaga agaaaaacca gagccctggc cctggccagg gatcggaggc tcctgagaag 4140

aagaaagcca agatcgatga gcttaaggtg taccccaagg agctggaatc ggagtttgac 4200

agctttgagg actggctgca caccttcaac ctgttgaggg gcaagacggg agatgatgag 4260

gatggctcca cagaggagga gcgcatagta ggccgattca agggctccct ctgtgtgtac 4320

aaagtgccac tcccagaaga tgtatctcga gaagctggct atgatcccac ctatggaatg 4380

ttccagggca tcccaagcaa tgaccccatc aatgtgctgg tccgaatcta tgtggtccgg 4440

gccacagacc tgcacccggc cgacatcaat ggcaaagctg acccctatat tgccatcaag 4500

ttaggcaaga ccgacatccg agacaaggag aactacatct ccaagcagct caaccctgtg 4560

tttgggaagt cctttgacat tgaggcctcc ttccccatgg agtccatgtt gacagtggcc 4620

gtgtacgact gggatctggt gggcactgat gacctcatcg gagaaaccaa gattgacctg 4680

gaaaaccgct tctacagcaa gcatcgcgcc acctgcggca tcgcacagac ctattccata 4740

catggctaca atatctggag ggaccccatg aagcccagcc agatcctgac acgcctctgt 4800

aaagagggca aagtggacgg cccccacttt ggtccccatg ggagagtgag ggttgccaac 4860

cgtgtcttca cggggccttc agaaatagag gatgagaatg gtcagaggaa gcccacagat 4920

gagcacgtgg cactgtctgc tctgagacac tgggaggaca tcccccgggt gggctgccgc 4980

cttgtgccgg aacacgtgga gaccaggccg ctgctcaacc ctgacaagcc aggcattgag 5040

cagggccgcc tggagctgtg ggtggacatg ttccccatgg acatgccagc ccctgggaca 5100

cctctggata tatcccccag gaaacccaag aagtacgagc tgcgggtcat cgtgtggaac 5160

acagacgagg tggtcctgga agacgatgat ttcttcacgg gagagaagtc cagtgacatt 5220

tttgtgaggg ggtggctgaa gggccagcag gaggacaaac aggacacaga tgtccactat 5280

cactccctca cgggggaggg caacttcaac tggagatacc tcttcccctt cgactaccta 5340

gcggccgaag agaagatcgt tatgtccaaa aaggagtcta tgttctcctg ggatgagacg 5400

gagtacaaga tccctgcgcg gctcaccctg cagatctggg acgctgacca cttctcggct 5460

gacgacttcc tgggggctat cgagctggac ctgaaccggt tcccgagggg cgctaagaca 5520

gccaagcagt gcaccatgga gatggccacc ggggaggtgg acgtacccct ggtttccatc 5580

tttaaacaga aacgtgtcaa aggctggtgg cccctcctgg cccgcaatga gaatgatgag 5640

tttgagctca caggcaaagt ggaggcggag ctacacctac tcacggcaga ggaggcagag 5700

aagaaccctg tgggcctggc tcgcaatgaa cctgatcccc tagaaaaacc caatcggccg 5760

gacacaagct tcatctggtt cttgaaccct ctcaagtctg cccgctactt cctgtggcat 5820

acctaccgct ggctactcct caaattcctg ctgctcttcc tcctgctgct gctcttcgcc 5880

ctgtttctct actctctgcc tggctacctg gccaagaaga tccttggggc ctga 5934

<210> 15

<211> 1977

<212> PRT

<213> 小家鼠（Mus musculus）

<400> 15

Met Ala Leu Ile Val His Leu Lys Thr Val Ser Glu Leu Arg Gly Lys

1 5 10 15

Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser

20 25 30

Arg Val Leu Glu Asn Cys Glu Gly Val Ala Asp Phe Asp Glu Thr Phe

35 40 45

Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Val Leu Glu Ile

50 55 60

Gln Ile Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr

65 70 75 80

Phe Cys Met Val Leu Gln Lys Val Val Glu Glu Asn Arg Val Glu Val

85 90 95

Thr Asp Thr Leu Met Asp Asp Ser Asn Ala Ile Ile Lys Thr Ser Leu

100 105 110

Ser Met Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Pro Trp

115 120 125

Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Lys Asp

130 135 140

Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Thr Arg

145 150 155 160

Ile Ser Gly Glu Lys Ser Phe Arg Arg Ala Gly Arg Ser Val Phe Ser

165 170 175

Ala Met Lys Leu Gly Lys Thr Arg Ser His Lys Glu Glu Pro Gln Arg

180 185 190

Gln Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu Ala

195 200 205

Ile Gln Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala Ser

210 215 220

Val Thr Ala Leu Thr Ser Asn Val Ser Asn Lys Arg Ser Lys Pro Asp

225 230 235 240

Ile Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val Ser

245 250 255

Ile Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp Pro

260 265 270

Val Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met Lys

275 280 285

Glu Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp Phe

290 295 300

His Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser Val

305 310 315 320

Ile His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser Phe

325 330 335

Lys Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe His

340 345 350

His Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ala Gly Leu

355 360 365

Lys Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp Asn

370 375 380

Ile Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile Glu

385 390 395 400

Gly Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp Ala

405 410 415

Arg Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met Asn

420 425 430

Thr Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn Lys

435 440 445

Asp Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys Gly

450 455 460

Lys Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu Gln

465 470 475 480

Val Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys Val

485 490 495

Gln Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr His

500 505 510

Phe Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe Leu

515 520 525

Pro Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg Asn

530 535 540

Tyr Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly Glu

545 550 555 560

Gly Val Ser Phe Arg Ala Arg Leu Met Leu Gly Leu Ala Val Glu Ile

565 570 575

Leu Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln Val

580 585 590

Glu Gln Ala Thr Pro Val Ser Glu Ser Cys Thr Gly Arg Met Glu Glu

595 600 605

Phe Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg Lys

610 615 620

Asn Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr Gly

625 630 635 640

Asn Glu Val Asp Gly Met Ser Arg Pro Leu Arg Pro Arg Pro Arg Lys

645 650 655

Glu Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ser Ser Asp

660 665 670

Asp Glu Gly Asp Glu Ala Gly Asp Leu Ala Ser Val Ser Ser Thr Pro

675 680 685

Pro Met Arg Pro Gln Ile Thr Asp Arg Asn Tyr Phe His Leu Pro Tyr

690 695 700

Leu Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp Gln

705 710 715 720

Arg Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp Lys

725 730 735

Leu Glu Glu Gly Leu Asn Asp Val Gln Glu Met Ile Lys Thr Glu Lys

740 745 750

Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser Cys

755 760 765

Gly Cys His Arg Phe Leu Ser Leu Ser Asp Lys Asp Gln Gly Arg Ser

770 775 780

Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg Glu

785 790 795 800

Leu Glu Ser Met Gly Gln Gln Ala Lys Ser Leu Arg Ala Gln Val Lys

805 810 815

Arg His Thr Val Arg Asp Lys Leu Arg Ser Cys Gln Asn Phe Leu Gln

820 825 830

Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp Val

835 840 845

Phe Ile Trp Met Met Ser Asn Asn Lys Arg Ile Ala Tyr Ala Arg Val

850 855 860

Pro Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Leu Gly Lys

865 870 875 880

Asp Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys Arg

885 890 895

Gly Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Leu Glu Leu Tyr

900 905 910

Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys Asp Phe Leu Cys Gly Leu

915 920 925

Pro Cys Gly Phe Glu Glu Val Lys Ala Ala Gln Gly Leu Gly Leu His

930 935 940

Ser Phe Pro Pro Ile Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe Gln

945 950 955 960

Leu Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp Ser

965 970 975

Ser Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln Ser

980 985 990

Gln Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp Gln

995 1000 1005

Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His Glu

1010 1015 1020

Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp Gln

1025 1030 1035

Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala Lys

1040 1045 1050

Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg Phe

1055 1060 1065

Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Ser Ala Thr

1070 1075 1080

Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro

1085 1090 1095

Ser Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Met

1100 1105 1110

Asp Arg Gly Pro Ile Met Pro Val Pro Val Gly Ile Arg Pro Val

1115 1120 1125

Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp

1130 1135 1140

Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp

1145 1150 1155

Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn

1160 1165 1170

Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe Glu

1175 1180 1185

Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn Ile

1190 1195 1200

Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val Gly

1205 1210 1215

Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro Pro

1220 1225 1230

Asp Arg Ser Ala Pro Asn Trp Asn Thr Thr Gly Glu Val Val Val

1235 1240 1245

Ser Met Glu Pro Glu Glu Pro Val Lys Lys Leu Glu Thr Met Val

1250 1255 1260

Lys Leu Asp Ala Thr Ser Asp Ala Val Val Lys Val Asp Val Ala

1265 1270 1275

Glu Asp Glu Lys Glu Arg Lys Lys Lys Lys Lys Lys Gly Pro Ser

1280 1285 1290

Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp Trp

1295 1300 1305

Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu

1310 1315 1320

Arg Gln His Glu Thr Ser Gly Thr Asp Leu Glu Glu Lys Glu Glu

1325 1330 1335

Met Glu Ser Ala Glu Gly Leu Lys Gly Pro Met Lys Ser Lys Glu

1340 1345 1350

Lys Ser Arg Ala Ala Lys Glu Glu Lys Lys Lys Lys Asn Gln Ser

1355 1360 1365

Pro Gly Pro Gly Gln Gly Ser Glu Ala Pro Glu Lys Lys Lys Ala

1370 1375 1380

Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys Glu Leu Glu Ser Glu

1385 1390 1395

Phe Asp Ser Phe Glu Asp Trp Leu His Thr Phe Asn Leu Leu Arg

1400 1405 1410

Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser Thr Glu Glu Glu Arg

1415 1420 1425

Ile Val Gly Arg Phe Lys Gly Ser Leu Cys Val Tyr Lys Val Pro

1430 1435 1440

Leu Pro Glu Asp Val Ser Arg Glu Ala Gly Tyr Asp Pro Thr Tyr

1445 1450 1455

Gly Met Phe Gln Gly Ile Pro Ser Asn Asp Pro Ile Asn Val Leu

1460 1465 1470

Val Arg Ile Tyr Val Val Arg Ala Thr Asp Leu His Pro Ala Asp

1475 1480 1485

Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile Lys Leu Gly Lys

1490 1495 1500

Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys Gln Leu Asn

1505 1510 1515

Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe Pro Met

1520 1525 1530

Glu Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val Gly

1535 1540 1545

Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg

1550 1555 1560

Phe Tyr Ser Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr

1565 1570 1575

Ser Ile His Gly Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser

1580 1585 1590

Gln Ile Leu Thr Arg Leu Cys Lys Glu Gly Lys Val Asp Gly Pro

1595 1600 1605

His Phe Gly Pro His Gly Arg Val Arg Val Ala Asn Arg Val Phe

1610 1615 1620

Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn Gly Gln Arg Lys Pro

1625 1630 1635

Thr Asp Glu His Val Ala Leu Ser Ala Leu Arg His Trp Glu Asp

1640 1645 1650

Ile Pro Arg Val Gly Cys Arg Leu Val Pro Glu His Val Glu Thr

1655 1660 1665

Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly Ile Glu Gln Gly Arg

1670 1675 1680

Leu Glu Leu Trp Val Asp Met Phe Pro Met Asp Met Pro Ala Pro

1685 1690 1695

Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys Pro Lys Lys Tyr Glu

1700 1705 1710

Leu Arg Val Ile Val Trp Asn Thr Asp Glu Val Val Leu Glu Asp

1715 1720 1725

Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser Asp Ile Phe Val Arg

1730 1735 1740

Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys Gln Asp Thr Asp Val

1745 1750 1755

His Tyr His Ser Leu Thr Gly Glu Gly Asn Phe Asn Trp Arg Tyr

1760 1765 1770

Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu Glu Lys Ile Val Met

1775 1780 1785

Ser Lys Lys Glu Ser Met Phe Ser Trp Asp Glu Thr Glu Tyr Lys

1790 1795 1800

Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp Asp Ala Asp His Phe

1805 1810 1815

Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu Leu Asp Leu Asn Arg

1820 1825 1830

Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln Cys Thr Met Glu Met

1835 1840 1845

Ala Thr Gly Glu Val Asp Val Pro Leu Val Ser Ile Phe Lys Gln

1850 1855 1860

Lys Arg Val Lys Gly Trp Trp Pro Leu Leu Ala Arg Asn Glu Asn

1865 1870 1875

Asp Glu Phe Glu Leu Thr Gly Lys Val Glu Ala Glu Leu His Leu

1880 1885 1890

Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro Val Gly Leu Ala Arg

1895 1900 1905

Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn Arg Pro Asp Thr Ala

1910 1915 1920

Phe Val Trp Phe Leu Asn Pro Leu Lys Ser Ile Lys Tyr Leu Ile

1925 1930 1935

Cys Thr Arg Tyr Lys Trp Leu Ile Ile Lys Ile Val Leu Ala Leu

1940 1945 1950

Leu Gly Leu Leu Met Leu Ala Leu Phe Leu Tyr Ser Leu Pro Gly

1955 1960 1965

Tyr Met Val Lys Lys Leu Leu Gly Ala

1970 1975

<210> 16

<211> 5934

<212> DNA

<213> 小家鼠（Mus musculus）

<400> 16

atggccctga ttgttcacct caagactgtc tcagagctcc gaggcaaagg tgaccggatt 60

gccaaagtca ctttccgagg gcagtctttc tactcccggg tcctggagaa ctgcgagggt 120

gtggctgact ttgatgagac gttccggtgg ccagtggcca gcagcatcga ccggaatgaa 180

gtgttggaga ttcagatttt caactacagc aaagtcttca gcaacaagct gatagggacc 240

ttctgcatgg tgctgcagaa agtggtggag gagaatcggg tagaggtgac cgacacgctg 300

atggatgaca gcaatgctat catcaagacc agcctgagca tggaggtccg gtatcaggcc 360

acagatggca ctgtgggccc ctgggatgat ggagacttcc tgggagatga atccctccag 420

gaggagaagg acagccagga gacagatggg ctgctacctg gttcccgacc cagcacccgg 480

atatctggcg agaagagctt tcgcagagcg ggaaggagtg tgttctcggc catgaaactc 540

ggcaaaactc ggtcccacaa agaggagccc caaagacaag atgagccagc agtgctggag 600

atggaggacc tggaccacct agccattcag ctgggggatg ggctggatcc tgactccgtg 660

tctctagcct cggtcaccgc tctcaccagc aatgtctcca acaaacggtc taagccagat 720

attaagatgg agcccagtgc tggaaggccc atggattacc aggtcagcat cacagtgatt 780

gaggctcggc agctggtggg cttgaacatg gaccctgtgg tgtgtgtgga ggtgggtgat 840

gacaagaaat acacgtcaat gaaggagtcc acaaactgcc cttactacaa cgagtacttt 900

gtcttcgact tccatgtctc tcctgatgtc atgtttgaca agatcatcaa gatctcggtt 960

atccattcta agaacctgct tcggagcggc accctggtgg gttccttcaa aatggatgtg 1020

gggactgtgt attcccagcc tgaacaccag ttccatcaca aatgggccat cctgtcagac 1080

cccgatgaca tctctgctgg gttgaagggt tatgtaaagt gtgatgtcgc tgtggtgggc 1140

aagggagaca acatcaagac accccacaag gccaacgaga cggatgagga cgacattgaa 1200

gggaacttgc tgctccccga gggcgtgccc cccgaacggc agtgggcacg gttctatgtg 1260

aaaatttacc gagcagaggg actgccccgg atgaacacaa gcctcatggc caacgtgaag 1320

aaggcgttca tcggtgagaa caaggacctc gtcgacccct atgtgcaagt cttctttgct 1380

ggacaaaagg gcaaaacatc agtgcagaag agcagctatg agccgctatg gaatgagcag 1440

gtcgtcttca cagacttgtt ccccccactc tgcaaacgca tgaaggtgca gatccgggac 1500

tctgacaagg tcaatgatgt ggccatcggc acccacttca tcgacctgcg caagatttcc 1560

aacgatggag acaaaggctt cctgcctacc ctcggtccag cctgggtgaa catgtacggc 1620

tccacgcgca actacacact gctggacgag caccaggact tgaatgaagg cctgggggag 1680

ggtgtgtcct tccgggcccg cctcatgttg ggactagctg tggagatcct ggacacctcc 1740

aacccagagc tcaccagctc cacggaggtg caggtggagc aggccacgcc tgtctcggag 1800

agctgcacag ggagaatgga agaatttttt ctatttggag ccttcttgga agcctcaatg 1860

attgaccgga aaaatgggga caagccaatt acctttgagg tgaccatagg aaactacggc 1920

aatgaagtcg atggtatgtc ccggcccctg aggcctcggc cccggaaaga gcctggggat 1980

gaagaagagg tagacctgat tcagaactcc agtgacgatg aaggtgacga agccggggac 2040

ctggcctcgg tgtcctccac cccacctatg cggccccaga tcacggacag gaactatttc 2100

cacctgccct acctggagcg caagccctgc atctatatca agagctggtg gcctgaccag 2160

aggcggcgcc tctacaatgc caacatcatg gatcacattg ctgacaagct ggaagaaggc 2220

ctgaatgatg tacaggagat gatcaaaacg gagaagtcct acccggagcg ccgcctgcgg 2280

ggtgtgctag aggaactcag ctgtggctgc caccgcttcc tctccctctc ggacaaggac 2340

cagggccgct cgtcccgcac caggctggat cgagagcgtc ttaagtcctg tatgagggag 2400

ttggagagca tgggacagca ggccaagagc ctgagggctc aggtgaagcg gcacactgtt 2460

cgggacaagc tgaggtcatg ccagaacttt ctgcagaagc tacgcttcct ggcggatgag 2520

ccccagcaca gcattcctga tgtgttcatt tggatgatga gcaacaacaa acgtatcgcc 2580

tatgcccgcg tgccttccaa agacctgctc ttctccatcg tggaggagga actgggcaag 2640

gactgcgcca aagtcaagac cctcttcctg aagctgccag ggaagagggg cttcggctcg 2700

gcaggctgga cagtacaggc caagctggag ctctacctgt ggctgggcct cagcaagcag 2760

cgaaaggact tcctgtgtgg tctgccctgt ggcttcgagg aggtcaaggc agcccaaggc 2820

ctgggcctgc attcctttcc gcccatcagc ctagtctaca ccaagaagca agccttccag 2880

ctccgagcac acatgtatca ggcccgaagc ctctttgctg ctgacagcag tgggctctct 2940

gatccctttg cccgtgtctt cttcatcaac cagagccaat gcactgaggt tctaaacgag 3000

acactgtgtc ccacctggga ccagatgctg gtatttgaca acctggagct gtacggtgaa 3060

gctcacgagt tacgagatga tccccccatc attgtcattg aaatctacga ccaggacagc 3120

atgggcaaag ccgacttcat gggccggacc ttcgccaagc ccctggtgaa gatggcagat 3180

gaagcatact gcccacctcg cttcccgccg cagcttgagt actaccagat ctaccgaggc 3240

agtgccactg ccggagacct actggctgcc ttcgagctgc tgcagattgg gccatcaggg 3300

aaggctgacc tgccacccat caatggccca gtggacatgg acagagggcc catcatgcct 3360

gtgcccgtgg gaatccggcc agtgctcagc aagtaccgag tggaggtgct gttctggggc 3420

ctgagggacc taaagagggt gaacctggcc caggtggacc gaccacgggt ggacatcgag 3480

tgtgcaggaa agggggtaca atcctccctg attcacaatt ataagaagaa ccccaacttc 3540

aacacgctgg tcaagtggtt tgaagtggac ctcccggaga atgagctcct gcacccaccc 3600

ttgaacatcc gagtggtaga ttgccgggcc tttggacgat acaccctggt gggttcccac 3660

gcagtcagct cactgaggcg cttcatctac cgacctccag accgctcagc ccccaactgg 3720

aacaccacag gggaggttgt agtaagcatg gagcctgagg agccagttaa gaagctggag 3780

accatggtga aactggatgc gacttctgat gctgtggtca aggtggatgt ggctgaagat 3840

gagaaggaaa ggaagaagaa gaaaaagaaa ggcccgtcag aggagccaga ggaggaagag 3900

cccgatgaga gcatgctgga ttggtggtcc aagtacttcg cctccatcga cacaatgaag 3960

gagcaacttc gacaacatga gacctctgga actgacttgg aagagaagga agagatggaa 4020

agcgctgagg gcctgaaggg accaatgaag agcaaggaga agtccagagc tgcaaaggag 4080

gagaaaaaga agaaaaacca gagccctggc cctggccagg gatcggaggc tcctgagaag 4140

aagaaagcca agatcgatga gcttaaggtg taccccaagg agctggaatc ggagtttgac 4200

agctttgagg actggctgca caccttcaac ctgttgaggg gcaagacggg agatgatgag 4260

gatggctcca cagaggagga gcgcatagta ggccgattca agggctccct ctgtgtgtac 4320

aaagtgccac tcccagaaga tgtatctcga gaagctggct atgatcccac ctatggaatg 4380

ttccagggca tcccaagcaa tgaccccatc aatgtgctgg tccgaatcta tgtggtccgg 4440

gccacagacc tgcacccggc cgacatcaat ggcaaagctg acccctatat tgccatcaag 4500

ttaggcaaga ccgacatccg agacaaggag aactacatct ccaagcagct caaccctgtg 4560

tttgggaagt cctttgacat tgaggcctcc ttccccatgg agtccatgtt gacagtggcc 4620

gtgtacgact gggatctggt gggcactgat gacctcatcg gagaaaccaa gattgacctg 4680

gaaaaccgct tctacagcaa gcatcgcgcc acctgcggca tcgcacagac ctattccata 4740

catggctaca atatctggag ggaccccatg aagcccagcc agatcctgac acgcctctgt 4800

aaagagggca aagtggacgg cccccacttt ggtccccatg ggagagtgag ggttgccaac 4860

cgtgtcttca cggggccttc agaaatagag gatgagaatg gtcagaggaa gcccacagat 4920

gagcacgtgg cactgtctgc tctgagacac tgggaggaca tcccccgggt gggctgccgc 4980

cttgtgccgg aacacgtgga gaccaggccg ctgctcaacc ctgacaagcc aggcattgag 5040

cagggccgcc tggagctgtg ggtggacatg ttccccatgg acatgccagc ccctgggaca 5100

cctctggata tatcccccag gaaacccaag aagtacgagc tgcgggtcat cgtgtggaac 5160

acagacgagg tggtcctgga agacgatgat ttcttcacgg gagagaagtc cagtgacatt 5220

tttgtgaggg ggtggctgaa gggccagcag gaggacaaac aggacacaga tgtccactat 5280

cactccctca cgggggaggg caacttcaac tggagatacc tcttcccctt cgactaccta 5340

gcggccgaag agaagatcgt tatgtccaaa aaggagtcta tgttctcctg ggatgagacg 5400

gagtacaaga tccctgcgcg gctcaccctg cagatctggg acgctgacca cttctcggct 5460

gacgacttcc tgggggctat cgagctggac ctgaaccggt tcccgagggg cgctaagaca 5520

gccaagcagt gcaccatgga gatggccacc ggggaggtgg acgtacccct ggtttccatc 5580

tttaaacaga aacgtgtcaa aggctggtgg cccctcctgg cccgcaatga gaatgatgag 5640

tttgagctca caggcaaagt ggaggcggag ctacacctac tcacggcaga ggaggcagag 5700

aagaaccctg tgggcctggc tcgcaatgaa cctgatcccc tagaaaaacc caaccggcct 5760

gacacggcat tcgtctggtt cctgaaccca ctcaaatcta tcaagtacct catctgcacc 5820

cggtacaagt ggctgatcat caagatcgtg ctggcgctgc tggggctgct catgctggcc 5880

ctcttccttt acagcctccc aggctacatg gtcaagaagc tcctaggggc ctga 5934

<210> 17

<211> 1997

<212> PRT

<213> 小家鼠（Mus musculus）

<400> 17

Met Ala Leu Ile Val His Leu Lys Thr Val Ser Glu Leu Arg Gly Lys

1 5 10 15

Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser

20 25 30

Arg Val Leu Glu Asn Cys Glu Gly Val Ala Asp Phe Asp Glu Thr Phe

35 40 45

Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Val Leu Glu Ile

50 55 60

Gln Ile Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr

65 70 75 80

Phe Cys Met Val Leu Gln Lys Val Val Glu Glu Asn Arg Val Glu Val

85 90 95

Thr Asp Thr Leu Met Asp Asp Ser Asn Ala Ile Ile Lys Thr Ser Leu

100 105 110

Ser Met Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Pro Trp

115 120 125

Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Lys Asp

130 135 140

Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Thr Arg

145 150 155 160

Ile Ser Gly Glu Lys Ser Phe Arg Arg Ala Gly Arg Ser Val Phe Ser

165 170 175

Ala Met Lys Leu Gly Lys Thr Arg Ser His Lys Glu Glu Pro Gln Arg

180 185 190

Gln Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu Ala

195 200 205

Ile Gln Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala Ser

210 215 220

Val Thr Ala Leu Thr Ser Asn Val Ser Asn Lys Arg Ser Lys Pro Asp

225 230 235 240

Ile Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val Ser

245 250 255

Ile Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp Pro

260 265 270

Val Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met Lys

275 280 285

Glu Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp Phe

290 295 300

His Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser Val

305 310 315 320

Ile His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser Phe

325 330 335

Lys Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe His

340 345 350

His Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ala Gly Leu

355 360 365

Lys Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp Asn

370 375 380

Ile Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile Glu

385 390 395 400

Gly Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp Ala

405 410 415

Arg Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met Asn

420 425 430

Thr Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn Lys

435 440 445

Asp Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys Gly

450 455 460

Lys Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu Gln

465 470 475 480

Val Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys Val

485 490 495

Gln Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr His

500 505 510

Phe Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe Leu

515 520 525

Pro Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg Asn

530 535 540

Tyr Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly Glu

545 550 555 560

Gly Val Ser Phe Arg Ala Arg Leu Met Leu Gly Leu Ala Val Glu Ile

565 570 575

Leu Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln Val

580 585 590

Glu Gln Ala Thr Pro Val Ser Glu Ser Cys Thr Gly Arg Met Glu Glu

595 600 605

Phe Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg Lys

610 615 620

Asn Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr Gly

625 630 635 640

Asn Glu Val Asp Gly Met Ser Arg Pro Leu Arg Pro Arg Pro Arg Lys

645 650 655

Glu Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ser Ser Asp

660 665 670

Asp Glu Gly Asp Glu Ala Gly Asp Leu Ala Ser Val Ser Ser Thr Pro

675 680 685

Pro Met Arg Pro Gln Ile Thr Asp Arg Asn Tyr Phe His Leu Pro Tyr

690 695 700

Leu Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp Gln

705 710 715 720

Arg Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp Lys

725 730 735

Leu Glu Glu Gly Leu Asn Asp Val Gln Glu Met Ile Lys Thr Glu Lys

740 745 750

Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser Cys

755 760 765

Gly Cys His Arg Phe Leu Ser Leu Ser Asp Lys Asp Gln Gly Arg Ser

770 775 780

Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg Glu

785 790 795 800

Leu Glu Ser Met Gly Gln Gln Ala Lys Ser Leu Arg Ala Gln Val Lys

805 810 815

Arg His Thr Val Arg Asp Lys Leu Arg Ser Cys Gln Asn Phe Leu Gln

820 825 830

Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp Val

835 840 845

Phe Ile Trp Met Met Ser Asn Asn Lys Arg Ile Ala Tyr Ala Arg Val

850 855 860

Pro Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Leu Gly Lys

865 870 875 880

Asp Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys Arg

885 890 895

Gly Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Leu Glu Leu Tyr

900 905 910

Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys Asp Phe Leu Cys Gly Leu

915 920 925

Pro Cys Gly Phe Glu Glu Val Lys Ala Ala Gln Gly Leu Gly Leu His

930 935 940

Ser Phe Pro Pro Ile Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe Gln

945 950 955 960

Leu Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp Ser

965 970 975

Ser Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln Ser

980 985 990

Gln Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp Gln

995 1000 1005

Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His Glu

1010 1015 1020

Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp Gln

1025 1030 1035

Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala Lys

1040 1045 1050

Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg Phe

1055 1060 1065

Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Ser Ala Thr

1070 1075 1080

Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro

1085 1090 1095

Ser Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Met

1100 1105 1110

Asp Arg Gly Pro Ile Met Pro Val Pro Val Gly Ile Arg Pro Val

1115 1120 1125

Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp

1130 1135 1140

Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp

1145 1150 1155

Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn

1160 1165 1170

Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe Glu

1175 1180 1185

Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn Ile

1190 1195 1200

Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val Gly

1205 1210 1215

Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro Pro

1220 1225 1230

Asp Arg Ser Ala Pro Asn Trp Asn Thr Thr Val Arg Leu Leu Arg

1235 1240 1245

Gly Cys His Arg Leu Arg Asn Gly Gly Pro Ser Ser Arg Pro Thr

1250 1255 1260

Gly Glu Val Val Val Ser Met Glu Pro Glu Glu Pro Val Lys Lys

1265 1270 1275

Leu Glu Thr Met Val Lys Leu Asp Ala Thr Ser Asp Ala Val Val

1280 1285 1290

Lys Val Asp Val Ala Glu Asp Glu Lys Glu Arg Lys Lys Lys Lys

1295 1300 1305

Lys Lys Gly Pro Ser Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu

1310 1315 1320

Ser Met Leu Asp Trp Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr

1325 1330 1335

Met Lys Glu Gln Leu Arg Gln His Glu Thr Ser Gly Thr Asp Leu

1340 1345 1350

Glu Glu Lys Glu Glu Met Glu Ser Ala Glu Gly Leu Lys Gly Pro

1355 1360 1365

Met Lys Ser Lys Glu Lys Ser Arg Ala Ala Lys Glu Glu Lys Lys

1370 1375 1380

Lys Lys Asn Gln Ser Pro Gly Pro Gly Gln Gly Ser Glu Ala Pro

1385 1390 1395

Glu Lys Lys Lys Ala Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys

1400 1405 1410

Glu Leu Glu Ser Glu Phe Asp Ser Phe Glu Asp Trp Leu His Thr

1415 1420 1425

Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser

1430 1435 1440

Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly Ser Leu Cys

1445 1450 1455

Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu Ala Gly

1460 1465 1470

Tyr Asp Pro Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn Asp

1475 1480 1485

Pro Ile Asn Val Leu Val Arg Ile Tyr Val Val Arg Ala Thr Asp

1490 1495 1500

Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala

1505 1510 1515

Ile Lys Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile

1520 1525 1530

Ser Lys Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu

1535 1540 1545

Ala Ser Phe Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp

1550 1555 1560

Trp Asp Leu Val Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile

1565 1570 1575

Asp Leu Glu Asn Arg Phe Tyr Ser Lys His Arg Ala Thr Cys Gly

1580 1585 1590

Ile Ala Gln Thr Tyr Ser Ile His Gly Tyr Asn Ile Trp Arg Asp

1595 1600 1605

Pro Met Lys Pro Ser Gln Ile Leu Thr Arg Leu Cys Lys Glu Gly

1610 1615 1620

Lys Val Asp Gly Pro His Phe Gly Pro His Gly Arg Val Arg Val

1625 1630 1635

Ala Asn Arg Val Phe Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn

1640 1645 1650

Gly Gln Arg Lys Pro Thr Asp Glu His Val Ala Leu Ser Ala Leu

1655 1660 1665

Arg His Trp Glu Asp Ile Pro Arg Val Gly Cys Arg Leu Val Pro

1670 1675 1680

Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly

1685 1690 1695

Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe Pro Met

1700 1705 1710

Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys

1715 1720 1725

Pro Lys Lys Tyr Glu Leu Arg Val Ile Val Trp Asn Thr Asp Glu

1730 1735 1740

Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser

1745 1750 1755

Asp Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys

1760 1765 1770

Gln Asp Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn

1775 1780 1785

Phe Asn Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu

1790 1795 1800

Glu Lys Ile Val Met Ser Lys Lys Glu Ser Met Phe Ser Trp Asp

1805 1810 1815

Glu Thr Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp

1820 1825 1830

Asp Ala Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu

1835 1840 1845

Leu Asp Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln

1850 1855 1860

Cys Thr Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val

1865 1870 1875

Ser Ile Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu

1880 1885 1890

Ala Arg Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu

1895 1900 1905

Ala Glu Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro

1910 1915 1920

Val Gly Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn

1925 1930 1935

Arg Pro Asp Thr Ser Phe Ile Trp Phe Leu Asn Pro Leu Lys Ser

1940 1945 1950

Ala Arg Tyr Phe Leu Trp His Thr Tyr Arg Trp Leu Leu Leu Lys

1955 1960 1965

Phe Leu Leu Leu Phe Leu Leu Leu Leu Leu Phe Ala Leu Phe Leu

1970 1975 1980

Tyr Ser Leu Pro Gly Tyr Leu Ala Lys Lys Ile Leu Gly Ala

1985 1990 1995

<210> 18

<211> 5994

<212> DNA

<213> 小家鼠（Mus musculus）

<400> 18

atggccctga ttgttcacct caagactgtc tcagagctcc gaggcaaagg tgaccggatt 60

gccaaagtca ctttccgagg gcagtctttc tactcccggg tcctggagaa ctgcgagggt 120

gtggctgact ttgatgagac gttccggtgg ccagtggcca gcagcatcga ccggaatgaa 180

gtgttggaga ttcagatttt caactacagc aaagtcttca gcaacaagct gatagggacc 240

ttctgcatgg tgctgcagaa agtggtggag gagaatcggg tagaggtgac cgacacgctg 300

atggatgaca gcaatgctat catcaagacc agcctgagca tggaggtccg gtatcaggcc 360

acagatggca ctgtgggccc ctgggatgat ggagacttcc tgggagatga atccctccag 420

gaggagaagg acagccagga gacagatggg ctgctacctg gttcccgacc cagcacccgg 480

atatctggcg agaagagctt tcgcagagcg ggaaggagtg tgttctcggc catgaaactc 540

ggcaaaactc ggtcccacaa agaggagccc caaagacaag atgagccagc agtgctggag 600

atggaggacc tggaccacct agccattcag ctgggggatg ggctggatcc tgactccgtg 660

tctctagcct cggtcaccgc tctcaccagc aatgtctcca acaaacggtc taagccagat 720

attaagatgg agcccagtgc tggaaggccc atggattacc aggtcagcat cacagtgatt 780

gaggctcggc agctggtggg cttgaacatg gaccctgtgg tgtgtgtgga ggtgggtgat 840

gacaagaaat acacgtcaat gaaggagtcc acaaactgcc cttactacaa cgagtacttt 900

gtcttcgact tccatgtctc tcctgatgtc atgtttgaca agatcatcaa gatctcggtt 960

atccattcta agaacctgct tcggagcggc accctggtgg gttccttcaa aatggatgtg 1020

gggactgtgt attcccagcc tgaacaccag ttccatcaca aatgggccat cctgtcagac 1080

cccgatgaca tctctgctgg gttgaagggt tatgtaaagt gtgatgtcgc tgtggtgggc 1140

aagggagaca acatcaagac accccacaag gccaacgaga cggatgagga cgacattgaa 1200

gggaacttgc tgctccccga gggcgtgccc cccgaacggc agtgggcacg gttctatgtg 1260

aaaatttacc gagcagaggg actgccccgg atgaacacaa gcctcatggc caacgtgaag 1320

aaggcgttca tcggtgagaa caaggacctc gtcgacccct atgtgcaagt cttctttgct 1380

ggacaaaagg gcaaaacatc agtgcagaag agcagctatg agccgctatg gaatgagcag 1440

gtcgtcttca cagacttgtt ccccccactc tgcaaacgca tgaaggtgca gatccgggac 1500

tctgacaagg tcaatgatgt ggccatcggc acccacttca tcgacctgcg caagatttcc 1560

aacgatggag acaaaggctt cctgcctacc ctcggtccag cctgggtgaa catgtacggc 1620

tccacgcgca actacacact gctggacgag caccaggact tgaatgaagg cctgggggag 1680

ggtgtgtcct tccgggcccg cctcatgttg ggactagctg tggagatcct ggacacctcc 1740

aacccagagc tcaccagctc cacggaggtg caggtggagc aggccacgcc tgtctcggag 1800

agctgcacag ggagaatgga agaatttttt ctatttggag ccttcttgga agcctcaatg 1860

attgaccgga aaaatgggga caagccaatt acctttgagg tgaccatagg aaactacggc 1920

aatgaagtcg atggtatgtc ccggcccctg aggcctcggc cccggaaaga gcctggggat 1980

gaagaagagg tagacctgat tcagaactcc agtgacgatg aaggtgacga agccggggac 2040

ctggcctcgg tgtcctccac cccacctatg cggccccaga tcacggacag gaactatttc 2100

cacctgccct acctggagcg caagccctgc atctatatca agagctggtg gcctgaccag 2160

aggcggcgcc tctacaatgc caacatcatg gatcacattg ctgacaagct ggaagaaggc 2220

ctgaatgatg tacaggagat gatcaaaacg gagaagtcct acccggagcg ccgcctgcgg 2280

ggtgtgctag aggaactcag ctgtggctgc caccgcttcc tctccctctc ggacaaggac 2340

cagggccgct cgtcccgcac caggctggat cgagagcgtc ttaagtcctg tatgagggag 2400

ttggagagca tgggacagca ggccaagagc ctgagggctc aggtgaagcg gcacactgtt 2460

cgggacaagc tgaggtcatg ccagaacttt ctgcagaagc tacgcttcct ggcggatgag 2520

ccccagcaca gcattcctga tgtgttcatt tggatgatga gcaacaacaa acgtatcgcc 2580

tatgcccgcg tgccttccaa agacctgctc ttctccatcg tggaggagga actgggcaag 2640

gactgcgcca aagtcaagac cctcttcctg aagctgccag ggaagagggg cttcggctcg 2700

gcaggctgga cagtacaggc caagctggag ctctacctgt ggctgggcct cagcaagcag 2760

cgaaaggact tcctgtgtgg tctgccctgt ggcttcgagg aggtcaaggc agcccaaggc 2820

ctgggcctgc attcctttcc gcccatcagc ctagtctaca ccaagaagca agccttccag 2880

ctccgagcac acatgtatca ggcccgaagc ctctttgctg ctgacagcag tgggctctct 2940

gatccctttg cccgtgtctt cttcatcaac cagagccaat gcactgaggt tctaaacgag 3000

acactgtgtc ccacctggga ccagatgctg gtatttgaca acctggagct gtacggtgaa 3060

gctcacgagt tacgagatga tccccccatc attgtcattg aaatctacga ccaggacagc 3120

atgggcaaag ccgacttcat gggccggacc ttcgccaagc ccctggtgaa gatggcagat 3180

gaagcatact gcccacctcg cttcccgccg cagcttgagt actaccagat ctaccgaggc 3240

agtgccactg ccggagacct actggctgcc ttcgagctgc tgcagattgg gccatcaggg 3300

aaggctgacc tgccacccat caatggccca gtggacatgg acagagggcc catcatgcct 3360

gtgcccgtgg gaatccggcc agtgctcagc aagtaccgag tggaggtgct gttctggggc 3420

ctgagggacc taaagagggt gaacctggcc caggtggacc gaccacgggt ggacatcgag 3480

tgtgcaggaa agggggtaca atcctccctg attcacaatt ataagaagaa ccccaacttc 3540

aacacgctgg tcaagtggtt tgaagtggac ctcccggaga atgagctcct gcacccaccc 3600

ttgaacatcc gagtggtaga ttgccgggcc tttggacgat acaccctggt gggttcccac 3660

gcagtcagct cactgaggcg cttcatctac cgacctccag accgctcagc ccccaactgg 3720

aacaccacag tcaggctgct ccggggctgc cacaggctgc gcaatggggg cccctcttct 3780

cgccccacag gggaggttgt agtaagcatg gagcctgagg agccagttaa gaagctggag 3840

accatggtga aactggatgc gacttctgat gctgtggtca aggtggatgt ggctgaagat 3900

gagaaggaaa ggaagaagaa gaaaaagaaa ggcccgtcag aggagccaga ggaggaagag 3960

cccgatgaga gcatgctgga ttggtggtcc aagtacttcg cctccatcga cacaatgaag 4020

gagcaacttc gacaacatga gacctctgga actgacttgg aagagaagga agagatggaa 4080

agcgctgagg gcctgaaggg accaatgaag agcaaggaga agtccagagc tgcaaaggag 4140

gagaaaaaga agaaaaacca gagccctggc cctggccagg gatcggaggc tcctgagaag 4200

aagaaagcca agatcgatga gcttaaggtg taccccaagg agctggaatc ggagtttgac 4260

agctttgagg actggctgca caccttcaac ctgttgaggg gcaagacggg agatgatgag 4320

gatggctcca cagaggagga gcgcatagta ggccgattca agggctccct ctgtgtgtac 4380

aaagtgccac tcccagaaga tgtatctcga gaagctggct atgatcccac ctatggaatg 4440

ttccagggca tcccaagcaa tgaccccatc aatgtgctgg tccgaatcta tgtggtccgg 4500

gccacagacc tgcacccggc cgacatcaat ggcaaagctg acccctatat tgccatcaag 4560

ttaggcaaga ccgacatccg agacaaggag aactacatct ccaagcagct caaccctgtg 4620

tttgggaagt cctttgacat tgaggcctcc ttccccatgg agtccatgtt gacagtggcc 4680

gtgtacgact gggatctggt gggcactgat gacctcatcg gagaaaccaa gattgacctg 4740

gaaaaccgct tctacagcaa gcatcgcgcc acctgcggca tcgcacagac ctattccata 4800

catggctaca atatctggag ggaccccatg aagcccagcc agatcctgac acgcctctgt 4860

aaagagggca aagtggacgg cccccacttt ggtccccatg ggagagtgag ggttgccaac 4920

cgtgtcttca cggggccttc agaaatagag gatgagaatg gtcagaggaa gcccacagat 4980

gagcacgtgg cactgtctgc tctgagacac tgggaggaca tcccccgggt gggctgccgc 5040

cttgtgccgg aacacgtgga gaccaggccg ctgctcaacc ctgacaagcc aggcattgag 5100

cagggccgcc tggagctgtg ggtggacatg ttccccatgg acatgccagc ccctgggaca 5160

cctctggata tatcccccag gaaacccaag aagtacgagc tgcgggtcat cgtgtggaac 5220

acagacgagg tggtcctgga agacgatgat ttcttcacgg gagagaagtc cagtgacatt 5280

tttgtgaggg ggtggctgaa gggccagcag gaggacaaac aggacacaga tgtccactat 5340

cactccctca cgggggaggg caacttcaac tggagatacc tcttcccctt cgactaccta 5400

gcggccgaag agaagatcgt tatgtccaaa aaggagtcta tgttctcctg ggatgagacg 5460

gagtacaaga tccctgcgcg gctcaccctg cagatctggg acgctgacca cttctcggct 5520

gacgacttcc tgggggctat cgagctggac ctgaaccggt tcccgagggg cgctaagaca 5580

gccaagcagt gcaccatgga gatggccacc ggggaggtgg acgtacccct ggtttccatc 5640

tttaaacaga aacgtgtcaa aggctggtgg cccctcctgg cccgcaatga gaatgatgag 5700

tttgagctca caggcaaagt ggaggcggag ctacacctac tcacggcaga ggaggcagag 5760

aagaaccctg tgggcctggc tcgcaatgaa cctgatcccc tagaaaaacc caatcggccg 5820

gacacaagct tcatctggtt cttgaaccct ctcaagtctg cccgctactt cctgtggcat 5880

acctaccgct ggctactcct caaattcctg ctgctcttcc tcctgctgct gctcttcgcc 5940

ctgtttctct actctctgcc tggctacctg gccaagaaga tccttggggc ctga 5994

<210> 19

<211> 35

<212> DNA

<213> 人工序列（Artificial Sequence）

<220>

<223> 引物A_F2

<400> 19

aattcaagct gctagcatgg ccctgattgt tcacc 35

<210> 20

<211> 27

<212> DNA

<213> 人工序列（Artificial Sequence）

<220>

<223> 引物A_R1

<400> 20

cgtttgttgt tgctcatcat ccaaatg 27

<210> 21

<211> 27

<212> DNA

<213> 人工序列（Artificial Sequence）

<220>

<223> 引物B_F1

<400> 21

gagcaacaac aaacgtatcg cctatgc 27

<210> 22

<211> 26

<212> DNA

<213> 人工序列（Artificial Sequence）

<220>

<223> 引物B_R1

<400> 22

gcagctcgta cttcttgggt ttcctg 26

<210> 23

<211> 26

<212> DNA

<213> 人工序列（Artificial Sequence）

<220>

<223> 引物C_F1

<400> 23

agaagtacga gctgcgggtc atcgtg 26

<210> 24

<211> 34

<212> DNA

<213> 人工序列（Artificial Sequence）

<220>

<223> 引物C_R2

<400> 24

gattatcgat aagcttttag gcccctagga gctt 34

Claims (15)

1.病毒载体，所述病毒载体包含核酸，所述核酸包含启动子以及与之可操作地连接的编码序列，所述编码序列编码全长Otoferlin或其功能片段或功能变体，其中，所述功能片段包含全长Otoferlin的至少1500个连续氨基酸残基，并且其中，所述功能变体包含与选自于由SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15和SEQ ID NO:17所组成的组中的氨基酸序列具有至少75％同一性的氨基酸序列。

2.根据权利要求1所述的病毒载体，其中，所述病毒载体选自于由以下所组成的组：腺相关病毒载体(AAV载体)、腺病毒载体、慢病毒载体、单纯疱疹病毒(HSV)载体、痘苗病毒载体和仙台病毒载体；其中，所述病毒载体优选为AAV载体或腺病毒载体。

3.根据权利要求2所述的病毒载体，其中，所述AAV载体选自于由AAV-PHP.B、AAV-PHP.eB、AAV-PHP.S和AAV-Anc80所组成的组。

4.根据权利要求2所述的病毒载体，其中，所述AAV载体选自于由AAV-8、AAV-9和AAV-1/2所组成的组。

5.根据权利要求1-4中任一项所述的病毒载体，其中，所述启动子选自于由以下所组成的组：巨细胞病毒(CMV)启动子，人β肌动蛋白/CMV杂合启动子，鸡β肌动蛋白/CMV杂合启动子，CMV-肌动蛋白-球蛋白(CAG)杂合启动子，Math1启动子，VGLUT3启动子，小白蛋白启动子，Calretinin启动子，Calbindin28k启动子，Prestin启动子，Otoferlin启动子，以及肌球蛋白II启动子、V启动子、VI启动子、VIIa启动子或XVa启动子。

6.根据权利要求1-5中任一项所述的病毒载体，其中，所述启动子为人β肌动蛋白/CMV杂合启动子。

7.根据权利要求1-6中任一项所述的病毒载体，其中，所述病毒载体为外泌体相关的病毒载体。

8.根据权利要求7所述的病毒载体，其中，所述病毒载体为exo-AAV载体。

9.药物组合物，所述药物组合物包含根据权利要求1-8中任一项所述的病毒载体和药学上可接受的载体或赋形剂。

10.用作药物的根据权利要求1-8中任一项所述的病毒载体或根据权利要求9所述的药物组合物。

11.根据权利要求1-8中任一项所述的病毒载体或根据权利要求9所述的药物组合物，所述病毒载体或药物组合物用于治疗基于Otoferlin基因(OTOF)的一种或多种突变的听力损失的方法。

12.根据权利要求11所述的病毒载体或药物组合物，其中，所述听力损失为DFNB9听力损失。

13.如权利要求11或12所述的病毒载体或药物组合物，其中，所述方法包括将所述病毒载体给予至内耳。

14.根据权利要求13所述的病毒载体或药物组合物，其中，所述给予包括：通过圆窗注射；经由镫骨切开术注射到前庭阶；经由耳蜗切开术注射到鼓阶；和/或以储积物形式应用到圆窗龛中，例如作为凝胶、海绵的组成部分，或者通过应用导管应用到圆窗龛中。

15.根据权利要求11-14中任一项所述的病毒载体或药物组合物，其中，所述给予使得全长Otoferlin或其功能片段或功能变体在耳蜗的内毛细胞中表达。

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