CN112351995A - 斯蒂尔综合征的啮齿动物模型 - Google Patents
斯蒂尔综合征的啮齿动物模型 Download PDFInfo
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- CN112351995A CN112351995A CN201980035497.1A CN201980035497A CN112351995A CN 112351995 A CN112351995 A CN 112351995A CN 201980035497 A CN201980035497 A CN 201980035497A CN 112351995 A CN112351995 A CN 112351995A
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Abstract
本公开涉及斯蒂尔综合征的啮齿动物模型。本文公开了经遗传修饰的啮齿动物,其携带在内源性啮齿动物Col27a1基因中的突变,所述突变等同于引起斯蒂尔综合征的人类突变。
Description
技术领域
本公开涉及人类疾病的动物模型。更具体地,本公开涉及斯蒂尔综合征(SteelSyndrome)的啮齿动物模型。本文公开了经遗传修饰的啮齿动物,其在内源性啮齿动物Col27a1基因中携带突变(等同于引起斯蒂尔综合征的人类突变)并且概括了在患有斯蒂尔综合征的人类中观察到的特征。
序列表以引用的方式并入
序列表为2019年5月21日创建的名称为35992PCT_10433WO01_SequenceListing、大小为75KB的ASCII文本文件,其经由EFS-Web提交给美国专利及商标局,并且以引用的方式并入本文。
背景技术
在整个说明书中引用了各种出版物,包括专利、专利申请、公开的专利申请、登录号、技术文章和学术文章。这些引用的出版物中的每一个出于所有目的均全文以引用方式并入本文件中。
斯蒂尔综合征(MIM#615155)最早由Steel等人于1993年描述为在波多黎各的23名西班牙裔儿童中观察到骨科综合征(Steel等人,J.Bone Joint Surg.Am.75:259-264,1993)。主要临床特征包括先天性双侧髋和桡头脱位、身材矮小、腕骨联合、脊柱侧弯、足部畸形和轻度畸形特点(mildly dysmorphic features)。
对STLS患者的临床和遗传评价指出了与其他特征明确的骨骼发育异常和结缔组织障碍不同的独特遗传综合征。鉴定STLS的特征性特点的常见分子病因的尝试一直未成功,直到2015年Gonzaga-Jauregui等人才报道,COL27A1 p.Gly697Arg变体当处于纯合状态时是斯蒂尔综合征的分子原因并表明这种错义变化是波多黎各人血统个体中的首建者变体(Gonzaga-Jauregui等人,Europ.J.Hum.Genet.23:342-346,2015)。随后在包括多族裔人群的大型群组中的研究在另外的个体中鉴定出p.Gly697Arg变体。已经发表了另外的案例,将COL27A1中的新型罕见隐性突变与骨软骨发育异常表型关联起来,所述表型的特征与已报道的波多黎各斯蒂尔综合征患者的特征重叠,而且还具有不能归因于斯蒂尔综合征的附加特征,诸如听力损失和言语延迟(Gariballa等人,Am J Med Genet A.2017;173(5):1257-1263;Kotabagi等人,Clin Genet.2017;92(3):323-326)。
发明内容
本公开涉及斯蒂尔综合征的啮齿动物模型。更具体地,本公开提供了在内源性啮齿动物Col27a1基因中携带突变(等同于导致人类斯蒂尔综合征的人COL27A1基因中的突变)的经遗传修饰的啮齿动物(例如,小鼠或大鼠)。
在一些实施方案中,本文公开了经遗传修饰的啮齿动物,其基因组包含内源性啮齿动物Col27a1基因中的突变,其中所述突变等同于导致在人COL27A1蛋白的氨基酸位置697处的Gly至Arg取代(G697R)的在人COL27A1基因中的突变。
在一些实施方案中,啮齿动物是小鼠或大鼠。在某些实施方案中,啮齿动物是小鼠,并且内源性小鼠Col27a1基因中的突变导致小鼠Col27a1蛋白中氨基酸位置682处的Gly至Arg取代。在其他实施方案中,啮齿动物是大鼠,并且内源性大鼠Col27a1基因中的突变导致大鼠Col27a1蛋白中氨基酸位置691处的Gly至Arg取代。
在一些实施方案中,啮齿动物是小鼠。在一些实施方案中,小鼠是C57BL品系的,例如C57BL/A、C57BL/An、C57BL/GrFa、C57BL/KaLwN、C57BL/6、C57BL/6J、C57BL/6ByJ、C57BL/6N、C57BL/6NJ、C57BL/10、C57BL/10ScSn、C57BL/10Cr和C57BL/Ola。在其他实施方案中,小鼠是129品系的,例如129P1、129P2、129P3、129X1、129S1(例如,129S1/SV、129S1/SvIm)、129S2、129S4、129S5、129S9/SvEvH、129/SvJae、129S6(129/SvEvTac)、129S7、129S8、129T1、129T2。在某些实施方案中,小鼠是前述129品系的混合体(即杂交体),或前述C57BL品系的混合体,或C57BL品系和129品系的混合体。在一些实施方案中,小鼠是C57BL/6N和129S6(129/SvEvTac)的杂交体。
在一些实施方案中,啮齿动物对于内源性啮齿动物Col27a1基因中的突变是杂合的。在其他实施方案中,啮齿动物对于内源性啮齿动物Col27a1基因中的突变是纯合的。
在一些实施方案中,啮齿动物是对于内源性小鼠Col27a1基因(例如,G682R)中的突变为杂合的C57BL/6N品系的小鼠。在一些实施方案中,啮齿动物是C57BL/6N和129S6(129/SvEvTac)的杂交体的并且对于内源性小鼠Col27a1基因(例如,G682R)是纯合的小鼠。
本文公开的啮齿动物(特别是对于与人COL27A1蛋白中编码G697R变异的突变等同的突变是纯合的啮齿动物、或对于所述突变是杂合的但不能表达野生型啮齿动物Col27a1蛋白的啮齿动物)表现出与斯蒂尔综合征相关的一种或多种异常。在一些实施方案中,所述异常选自由以下项组成的组:如与野生型啮齿动物相比,在3周龄时在脊柱中的严重胸椎后凸、体长减小、长骨长度降低、骨矿物质含量(BMC)降低、和体重减轻。
在一些实施方案中,本文公开了分离的啮齿动物细胞或组织,其基因组包含内源性啮齿动物Col27a1基因中的突变,其中所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变。分离的细胞或组织可以是小鼠或大鼠的分离的细胞或组织。
在一些实施方案中,本文公开了分离的啮齿动物胚胎干细胞,其基因组包含内源性啮齿动物Col27a1基因中的突变,其中所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变。分离的啮齿动物胚胎干细胞可以是小鼠或大鼠胚胎干细胞。
在一些实施方案中,本文公开了制备Col27a1突变型啮齿动物的方法,所述方法包括修饰啮齿动物基因组使得经修饰的基因组包含内源性啮齿动物Col27a1基因中的突变,所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变;以及制备包含经修饰的基因组的Col27a1突变型啮齿动物。在一些实施方案中,通过将靶向核酸引入啮齿动物ES细胞的基因组中来修饰啮齿动物基因组,以获得其基因组包含内源性啮齿动物Col27a1基因中的突变的突变型啮齿动物ES细胞;以及使用(a)的突变型啮齿动物ES细胞来制备Col27a1突变型啮齿动物。本申请的方法可以用于制备突变型小鼠或大鼠。
在一些实施方案中,本文公开了靶向核酸构建体,所述靶向核酸构建体包含将要在内源性啮齿动物Col27a1基因座处整合到啮齿动物Col27a1基因中的核酸序列,其侧翼为与啮齿动物Col27a1基因座处的核苷酸序列同源的5’核苷酸序列和3’核苷酸序列,其中所述核酸序列整合到所述啮齿动物Col27a1基因中导致内源性啮齿动物Col27a1基因中的突变,所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变。可以设计靶向核酸构建体以将所述核酸序列在内源性小鼠或大鼠Col27a1基因座处整合到小鼠或大鼠Col27a1基因中。
在进一步的实施方案中,本文公开了鉴定用于治疗斯蒂尔综合征的治疗剂的方法,所述方法包括向本文公开的啮齿动物施用药剂,进行一种或多种测定以确定所述药剂是否对与啮齿动物中的斯蒂尔综合征相关的一种或多种异常具有效果;以及当所述药剂对与斯蒂尔综合征相关的一种或多种异常具有治疗效果时将所述药剂鉴定为治疗剂。在一些实施方案中,在出生时或出生后不久,例如出生后15、14、13、12、11、10、9、8、7、6、5、4、3、2天或1天内,将所述药剂施用至啮齿动物。
附图说明
本专利文件含有至少一个用彩色表现的附图。本专利带有彩色附图的副本将会根据要求且在支付必要的费用后由专利及商标局提供。
图1描绘了人COL27A1蛋白的结构域结构(层粘连蛋白G结构域、胶原蛋白的三螺旋结构域特征、和原纤维胶原C末端结构域)、以及pG697R突变的位置。
图2A-2D描绘了Col27a1敲入突变型小鼠的总体表型。(A)纯合的Col27a1G682R/G682R小鼠显示出明显的侏儒症,杂合的Col27a1G682R/+小鼠在表型上是正常的并且在3周龄时与野生型同窝幼仔没有区别。(B)突变型和野生型的背侧和侧面μCt图像,其中纯合突变型小鼠显示出驼背、短吻部和圆形头骨。(C-D)纯合和杂合KI小鼠与野生型同窝幼仔的长度、体重和骨骼参数(骨矿物质含量(BMC)和骨矿物质密度(BMD))的纵向监测。纯合的Col27a1G682R/G682R小鼠显示出体重和BMC降低。
图3示出了来自Col27a1 G682R KI小鼠的长骨的组织学分析。与野生型和杂合的KI同窝幼仔相比,纯合的Col27a1G682R/G682R KI小鼠显示出软骨发育不全,伴有增殖区减少和破坏以及柱状软骨细胞完全不存在。番红精(Safranin-O)和von-Kossa染色剂的组织化学比较显示基因型之间蛋白聚糖积累和矿化作用分别没有明显差异。
图4描绘了用于将G697R直系同源突变(G682R)引入小鼠野生型Col27a1等位基因中的示例性靶向策略。
图5A-5D列出了人、小鼠和大鼠Col27a1蛋白序列(分别为SEQ ID NO:2、4和6)的比对。高亮显示(在编号为708的位置)了人COL27A1中的甘氨酸697、小鼠Col27a1中的甘氨酸682和大鼠Col27a1中的Gly 691。
具体实施方式
本文公开了斯蒂尔综合征的啮齿动物模型。特别地,本文公开了在内源性啮齿动物Col27a1基因中具有突变的啮齿动物,所述突变等同于引起人的斯蒂尔综合征的在人COL27A1基因中的突变(例如p.Gly697Arg)。本文公开的啮齿动物概括了在患有斯蒂尔综合征的人类中观察到的临床特点,并且可用于鉴定和开发用于治疗和/或改善斯蒂尔综合征和其他骨骼障碍的候选治疗剂。
在以下章节中详细描述了本公开的各个方面。
COL27A1
胶原是细胞外基质中最丰富的蛋白质,并且是脊椎动物结缔组织的结构和支架的主要贡献者。胶原蛋白可以被细分为不同的家族,但全部都享有相似的结构,所述结构的特征在于重复三氨基酸(Gly-Xaa-Yaa)的三螺旋结构域(Gariballa等人,Am J Med GenetA.2017;173(5):1257-1263;Gonzaga-Jauregui等人,同上)。
胶原XXVII型α1(COL27A1)是原纤维胶原家族的成员。胶原XXVII型在发育的软骨中高度表达,并且在其他组织中以较少的程度表达(Pace等人,Matrix Biol.22:3-14,2003;Boot-Handford等人,J.Biol.Chem.278:31067-77,2003;Plumb等人,J.Biol.Chem.282:12791-12795,2007;以及Hjorten等人,Bone 41:535-542,2007)。基于表达模式,已经假设COL27A1在软骨矿化期间可能起着重要作用,为其他细胞类型进入和血管入侵提供支架以便形成骨骼结构。斑马鱼和小鼠已被用于研究Col27a1基因的潜在功能丧失的影响。这些研究表明,COL27A1在骨骼系统形成和发育中起着重要作用(Christiansen等人,PLoS ONE 4(12):1-10,2009;Plumb等人,PLoS ONE9422,2011)。
人COL27A1基因位于9q32-33处,长度为约156kb,由61个外显子构成,并且编码1860个氨基酸的前肽。所述蛋白质具有胶原的特征结构;然而,如与其他原α(proalpha)胶原蛋白(1012个氨基酸)相比其三螺旋结构域较短(990个氨基酸)。同源小鼠基因位于4号染色体上,并且编码1845个氨基酸的蛋白质。Col27a1在物种之间高度保守。例如,人和小鼠的COL27A1蛋白都包括信号肽、层粘连蛋白G结构域(对于人为175个残基和对于小鼠为178个残基)、三螺旋结构域(对于人为994个残基和对于小鼠为997个残基,在Gly-X-Y重复序列中有两个保守中断)、以及NC1结构域或C前肽(对于人为239个残基和对于小鼠为242个残基,具有8个特征性半胱氨酸残基)。参见表1(对来自人、小鼠和大鼠的Col27A1蛋白的特征的概述)和图5A-5D(人、小鼠和大鼠Col27A1蛋白序列的比对)。
来自人、小鼠和大鼠的示例性COL27A1 mRNA和蛋白序列可在GenBank中从以下登录号获得,并且在序列表中也示为SEQ ID NO:1-6。
表1
斯蒂尔综合征和在人COL27A1中的致病突变
斯蒂尔综合征(MIM#615155)最早由Steel等人于1993年描述为在波多黎各的23名西班牙裔儿童中观察到骨科综合征(Steel等人,J.Bone Joint Surg.Am.75:259-264,1993)。主要临床特征包括先天性双侧髋和桡头脱位、身材矮小、腕骨联合、脊柱侧弯、足部畸形和轻度畸形特点(mildly dysmorphic features)。先天性髋关节脱位的标准治疗是手术干预,通常效果较差(Gonzaga-Jauregui等人,Europ.J.Hum.Genet.23:342-346,2015)。
术语“突变”包括基因中一个或多个核苷酸的添加、缺失或取代。在一些实施方案中,突变是单个核苷酸的取代。在其他实施方案中,突变是一个或多个核苷酸的缺失。在一些实施方案中,基因中的突变导致编码蛋白中一个或多个氨基酸的添加、缺失或取代以提供突变蛋白。在一些实施方案中,基因中的突变导致编码蛋白中氨基酸的取代。在其他实施方案中,基因中的突变导致一个或多个氨基酸的缺失。在某些实施方案中,基因中的突变(例如,核苷酸的取代)是无义突变,即,所述改变编码导致截短蛋白质的提前终止密码子。在一些实施方案中,基因中的突变(例如一个或多个核苷酸的添加或缺失)导致阅读框中的移码,从而产生如与野生型蛋白质产物相比被截短或延长或具有不同氨基酸序列的突变蛋白。在仍其他实施方案中,基因中的突变也可能例如通过改变供体或受体位点来影响剪接,从而产生不同剪接的mRNA转录物,因而产生不同的蛋白质产物。
根据本公开,导致斯蒂尔综合征的人COL27A1基因中的突变是与斯蒂尔综合征关联并分离的人COL27A1基因中的突变。这种突变在本文中也称为致病突变。
当Gonzaga-Jauregui等人于2015年在由两个同胞及其表兄弟姐妹(全部均患有斯蒂尔综合征)共享的COL27A1基因中鉴定出纯合的罕见错义变体(c.2089G>C,在外显子7中;p.G697R)时,在人COL27A1中的突变首次与斯蒂尔综合征关联(Gonzaga-Jauregui等人,Europ.J.Hum.Genet.23:342-346,2015)。早先在人群数据库中以杂合状态以低频率报道了此变体,并且所述变体在杂合携带者中似乎没有任何可见的表型作用。Gonzaga-Jauregui等人得出结论,当是纯合型时,COL27A1 p.Gly697Arg变体是斯蒂尔综合征的分子原因。
随后在包括多族裔人群的大型群组中的研究在另外的个体中鉴定出p.Gly697Arg变体(Belbin等人,eLife 2017;6.pii:e25060)。本文在实施例中描述的研究证明了此变体在多名受影响个体中的纯合性和分离,进一步证实了变体等位基因代表首建者突变,并且是斯蒂尔综合征的分子原因。
p.Gly697Arg变体是改变高度保守甘氨酸残基的取代,所述甘氨酸残基是胶原蛋白三螺旋结构域的Gly-Xaa-Yaa重复基序特征的一部分。参见例如,Gonzaga-Jauregui等人,同上的图3(b)-(c)。不受任何特定理论的束缚,当分泌到骨生长板肥大区域的细胞外基质中时Gly697Arg取代可能导致蛋白质错误折叠,从而引起功能异常,因而产生在人类患者和啮齿动物小鼠模型中观察到的异常生长表型。
包含与在人类中导致斯蒂尔综合征的突变等同的在内源性Col27a1中的突变的啮齿动物
如本文中所证明的,可以将与导致斯蒂尔综合征的在人COL27A1基因中的突变等同的突变引入啮齿动物的内源性Col27a1基因中,并致使啮齿动物表现出在人类中观察到的特征,诸如斯蒂尔综合征的骨骼异常特征。
在一些实施方案中,人COL27A1基因中的致病突变是错义突变。在一些实施方案中,人COL27A1基因中的致病突变是导致人COL27A1的氨基酸位置697处的甘氨酸被精氨酸取代的突变。
“等同的”意指在啮齿动物Col27a1基因中的突变导致与在人类中相同的错义取代,例如,在啮齿动物Col27a1蛋白中与人COL27A1蛋白中的氨基酸位置697对应的氨基酸位置处用精氨酸取代甘氨酸。例如,根据登录号NP_079961.3,与Gly697Arg人类突变等同的小鼠Col27a1基因突变是导致小鼠Col27a1蛋白的位置682处的Gly被取代为Arg的突变,并且根据登录号NP_116277.2,与Gly697Arg人类突变等同的大鼠Col27a1基因突变是导致在大鼠Col27a1蛋白的位置691处的Gly被取代为Arg的突变。
人们可以容易确定啮齿动物Col27a1蛋白中与人COL27A1蛋白中给定氨基酸位置对应的氨基酸位置。各种序列比对工具在本领域中是可用的,包括在商业计算机程序中可用的那些,诸如用于核苷酸序列的BLASTN,以及用于氨基酸序列的BLASTP、带缺口的BLAST和PSI-BLAST。示例性程序在以下文献中进行了描述:在Altschul,S.F.等人,1997,Methodsin Enzymology;Baxevanis,A.D.和B.F.F.Ouellette(编辑)Bioinformatics:A PracticalGuide to the Analysis of Genes and Proteins,Wiley,1998;以及Misener等人(编辑)Bioinformatics Methods and Protocols(Methods in Molecular Biology,第132卷),Humana Press,1998。为了说明,在图5A-5D中提供了使用多重全局序列比对ClustalW程序对人COL27A1蛋白(SEQ ID NO:2)、小鼠Col27a1蛋白(SEQ ID NO:4)和大鼠Col27a1(SEQ IDNO:6)的比对。
在一些实施方案中,本文公开的含有与人COL27A1基因中的致病突变等同的在内源性啮齿动物Col27a1基因中的突变的啮齿动物对于此突变可以是杂合的或纯合的。
在一些实施方案中,本文公开的啮齿动物不能表达野生型啮齿动物Col27a1蛋白。例如,提供了其中内源性啮齿动物Col27a1基因的一个拷贝含有等同于致病性人类突变的突变而另一拷贝被破坏或缺失的啮齿动物。或者,啮齿动物对于与人COL27A1基因中的致病突变等同的突变是纯合的,并且因此不能表达野生型啮齿动物Col27a1蛋白。
由携带与在人COL27A1中的致病突变等同的突变且不能表达野生型Col27a1蛋白,本文提供的啮齿动物表现出在人类中观察到的具有斯蒂尔综合征特征的特点。在一些实施方案中,本文公开的啮齿动物在人类中表现出斯蒂尔综合征的一种或多种异常特征,例如,以下骨骼异常中的一种或多种:与野生型(对照)啮齿动物相比,在3周龄时展现出的脊柱中的严重胸椎后凸、身长减少、长骨长度降低、骨矿物质含量(BMC)降低、生长板缺陷和体重减轻。在一些实施方案中,受试者啮齿动物的颅面异常包括较短的吻部和略呈圆形的圆顶形头骨,这可以在胚胎期(例如,胚胎第18.5天)中尽早观察到。在一些实施方案中,啮齿动物中生长板的缺陷包括增殖区正常结构的丧失以及柱状软骨细胞的缺乏和/或破坏。在任何上述参数中,突变型啮齿动物与野生型啮齿动物之间的差异是显著的,即,突变型啮齿动物中的参数与野生型啮齿动物中的相同参数相差了至少约15%、20%、25%、30%、40%、45%、50%、55%、60%、65%、70%、75%或更多。
本文提供的啮齿动物包括例如小鼠、大鼠和仓鼠。在一些实施方案中,啮齿动物是小鼠或大鼠。在具体的实施方案中,啮齿动物是小鼠。
在一些实施方案中,啮齿动物是C57BL品系的,例如选自以下项的C57BL品系的小鼠:C57BL/A、C57BL/An、C57BL/GrFa、C57BL/KaLwN、C57BL/6、C57BL/6J、C57BL/6ByJ、C57BL/6N、C57BL/6NJ、C57BL/10、C57BL/10ScSn、C57BL/10Cr和C57BL/Ola。在其他实施方案中,啮齿动物是129品系(例如选自由以下项组成的组的129品系)的小鼠:129P1、129P2、129P3、129X1、129S1(例如129S1/SV、129S1/SvIm)、129S2、129S4、129S5、129S9/SvEvH、129/SvJae、129S6(129/SvEvTac)、129S7、129S8、129T1、129T2(参见例如,Festing等人(1999),Mammalian Genome 10:836;Auerbach等人(2000),Biotechniques 29(5):1024-1028,1030,1032)。在一些实施方案中,啮齿动物是前述129品系和前述C57BL/6品系的混合体的小鼠。在某些实施方案中,小鼠是前述129品系的混合体(即杂交体),或前述C57BL品系的混合体,或C57BL品系和129品系的混合体。在某些实施方案中,小鼠是C57BL/6品系与129品系的混合体。在具体的实施方案,小鼠是VGF1品系,也称为F1H4品系,其是C57BL/6和129的杂交体。在具体的实施方案中,小鼠是C57BL/6N和129S6(129/SvEvTac)的杂交体。在其他实施方案中,小鼠是BALB品系,例如BALB/c品系。在一些实施方案中,小鼠是BALB品系和另一种前述品系的混合体。
在一些实施方案中,啮齿动物是大鼠。在某些实施方案中,大鼠选自Wistar大鼠、LEA品系、Sprague Dawley品系、Fischer品系、F344、F6和Dark Agouti。在其他实施方案中,大鼠是选自由Wistar、LEA、Sprague Dawley、Fischer、F344、F6和Dark Agouti组成的组的两个或更多个品系的混合体。
用于制备包含突变的啮齿动物的靶向载体和方法
可以使用本文公开的方法制备本文提供的啮齿动物。在示例性实施方案中,构建了携带含有所需突变的啮齿动物Col27a1核酸序列的靶向载体。除含有突变的啮齿动物Col27a1核酸序列外,靶向载体还可以包括在内源性啮齿动物Col27a1基因座处具有适当长度且与啮齿动物Col27A1基因序列同源的侧翼核酸序列,以便能够介导含有突变的啮齿动物Col27A1核酸序列的同源重组和整合到内源性啮齿动物Col27a1基因中。
在一些实施方案中,将包含啮齿动物Col27a1基因突变的核酸分子(例如,插入核酸)插入载体(优选DNA载体)中。根据大小,突变型啮齿动物Col27a1基因序列可以直接从cDNA来源克隆,或者可以基于可获自GenBank的公开序列(见上文)计算机模拟设计。或者,细菌人工染色体(BAC)文库可以提供啮齿动物Col27a1基因序列。啮齿动物Col27A1基因序列也可以从酵母人工染色体(YAC)中分离、克隆和/或转移。
在一些实施方案中,插入核酸还含有选择标记基因(例如,含有选择标记基因的自缺失盒,如美国专利号8,697,851、8,518,392和8,354,389中所述,其全部以引用的方式并入本文),其可能侧翼为或包含位点特异性重组位点(例如,loxP、Frt等)。可以将选择标记基因置于突变附近的载体上,以使转染子易于选择。
在图4中示出了示例性靶向载体。
在一些实施方案中,可以通过例如电穿孔将携带突变型啮齿动物Col27a1基因序列的BAC载体引入啮齿动物胚胎干(ES)细胞中。本领域已经描述了小鼠ES细胞和大鼠ES细胞。参见,例如US 7,576,259、US7,659,442、US 7,294,754和US 2008-0078000A1(所有所述专利均以引用的方式并入本文)描述了小鼠ES细胞和用于制备经基因修饰的小鼠的方法;以及US 2014/0235933A1和US 2014/0310828A1(所有所述专利均以引用的方式并入本文)描述了大鼠ES细胞和制备经基因修饰的大鼠的方法。
通过在整合位点引入染色体DNA的断裂可以促进受体细胞中的同源重组,这可以通过将某些核酸酶靶向整合的特异性位点来实现。在目标基因座识别DNA序列的DNA结合蛋白是本领域中已知的。在一些实施方案中,利用识别靶序列中特定的3-核苷酸序列的锌指核酸酶(ZFN)。在一些实施方案中,将转录活化因子样(TAL)效应子核酸酶(TALEN)用于位点特异性基因组编辑。在其他实施方案中,利用由组分(Cas9和tracrRNA)和靶标特异性CRISPR RNA(crRNA)组成的RNA引导核酸内切酶(RGEN)。
在一些实施方案中,将侧翼为5'和3'同源臂的携带目的核酸(例如,含有待引入突变的核酸)的靶向载体与一种或多种另外的载体或mRNA一起引入细胞中。在一个实施方案中,所述一个或多个额外载体或mRNA含有编码位点特异性核酸酶的核苷酸序列,所述位点特异性核酸酶包括(但不限于)锌指核酸酶(ZFN)、ZFN二聚体、转录活化因子样效应子核酸酶(TALEN)、TAL效应子结构域融合蛋白和RNA指导的DNA核酸内切酶。
可以选择具有整合在基因组中的突变型基因序列的ES细胞。选择之后,可以修饰阳性ES克隆,例如,如果需要,以去除自缺失盒随后将具有整合在基因组中的突变的ES细胞用作供体ES细胞以通过使用方法(参见例如US 7,576,259、US 7,659,442、US 7,294,754和US 2008/0078000A1)或US 2014/0235933A1和US 2014/0310828A1中描述的方法注射到桑椹胚前期胚胎(例如,8细胞期胚胎)中。孵育包含供体ES细胞的胚胎直至胚泡期,然后植入到代理孕母体中以产生完全源自供体ES细胞的F0啮齿动物。使用检测突变序列或选择标记基因的存在的等位基因修饰(MOA)测定(Valenzuela等人,同上),通过对从剪尾分离的DNA进行基因分型,可以鉴定出具有突变等位基因的啮齿动物幼崽。
用作斯蒂尔综合征的啮齿动物模型
本文提供的啮齿动物允许更好地理解斯蒂尔综合征发展的潜在分子机制。另外,此类啮齿动物可以用于筛选和开发用于预防和治疗斯蒂尔综合征和其他骨骼障碍(例如,生长不足、关节炎、骨质疏松症、脊柱侧弯、颈痛等)的治疗剂。
在一些实施方案中,通过向本文公开的啮齿动物(即,携带与人COLA27A1基因中的致病突变等同的在内源性啮齿动物Col27a1基因中的突变的啮齿动物)施用所述药剂来体内确定候选治疗剂的效果。在一些实施方案中,候选治疗剂是核酸分子,例如COL27A1基因疗法药物。
在一些实施方案中,本文所述的啮齿动物被用于确定和/或优化一种或多种候选基因疗法药物的载体设计。
在一些实施方案中,本文所述的啮齿动物被用于确定候选药物(例如基因疗法药物)的药代动力学特性。药代动力学性质包括但不限于非人类动物将药物处理成多种代谢物的方式(或一种或多种药物代谢物,包括但不限于毒性代谢物的存在或不存在的检测)、药物半衰期、施用后药物的循环水平(例如药物的血清浓度)、抗药物应答(例如抗药物抗体)、药物吸收和分布、施用途径、排泄途径和/或药物清除。
候选药物(例如,COL27A1基因疗法药物)可以经由任何期望的施用途径(包括用于在本文所述的非人类动物中进行评估的肠胃外和非肠胃外施用途径)给药。肠胃外途径包括例如静脉内、动脉内、门静脉内、肌肉内、皮下、腹膜内、脊柱内、鞘内、脑室内、颅内、胸膜内或其他注射途径。非肠胃外途径包括例如口服、鼻腔、透皮、肺部、直肠、面颊、阴道、眼部。施用也可以通过连续输注、局部施用、从植入物(凝胶、膜等)持续释放和/或静脉内注射来进行。可以使用从所描述的啮齿动物获得的样品进行各种测定以确定所施用药物的药代动力学特征。
在一些实施方案中,在出生时或出生后不久(例如,在出生后15天、14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天、2天或1天内)将候选药物(例如,基因疗法药物)给予本文所述的啮齿动物。可以在不同的时间点(例如,0小时、6小时、1天、2天、3天、4天、5天、10天、15天、30天、60天、90天、至长达6-12个月或更长时间)进行各种功能和/或形态测定或分析,以确定候选药物对于携带与人类的致病突变等同的Col27a1突变的啮齿动物在抑制本文所述异常的发展和/或进展方面的效果。
在一些实施方案中,进行测定包括确定施用药物的携带突变的啮齿动物与(i)未施用药物的携带突变的啮齿动物、(ii)对于所述突变为杂合的啮齿动物和/或没有突变的啮齿动物(即野生型啮齿动物)之间的差异。
通过以下实施例进一步说明本说明书,所述实施例不应解释为以任何方式具有限制性。所有引用文献(包括贯穿本申请所引用的参考文献、发布的专利和公布的专利申请)的内容特此以引用的方式明确并入。
实施例1.在另外的斯蒂尔综合征患者中COL27A1(p.Gly697Arg)变体的确认
最初发现一种罕见的COL27A1错义变体p.Gly697Arg以纯合子存在于患有斯蒂尔综合征的单一家庭的三个成员中,并且随后被证实是所述疾病的分子原因。
获得了Steel于1993年报道的6例原始STLS患者及其可及家庭成员的样品并进行了基因分型。发现六名患者中有五名对于p.Gly697Arg变体是纯合的,并且其在这些波多黎各家庭中根据孟德尔对常染色体隐性遗传疾病的预期分离。此外,还通过全外显子组测序和靶向突变测试分析了另外4名基于临床表现患有疑似斯蒂尔综合征的波多黎各人后裔患者的样品。还发现这些个体对于COL27A1中的p.Gly697Arg变体是纯合的。
总之,文献中总共报道了40例患者,其临床发现与Steel在50年前报道的“波多黎各人综合征”相对应。在这些患者中有17名已经被分子确认并且报道为对于COL27A1中的p.Gly697Arg变体是纯合的,全部都是波多黎各人血统,证实了此疾病的首建者效应假说。所报道的病例还记录了基因型-表型关联的特异性,这相对统一的临床表型相一致,所述临床表型的主要特征是身材矮小、双侧先天性髋关节发育异常、腕骨联合、桡头脱位、脊柱侧弯、足部畸形和椎骨异常。
实施例2.斯蒂尔综合征p.Gly697Arg变体的体内小鼠建模
Col27a1突变型小鼠的产生。为了模拟人p.Gly697Arg变体,将导致p.Gly682Arg取代的鸟嘌呤至胞苷突变(与人类突变直向同源)引入鼠Col27a1基因的高度保守的三螺旋结构域中。使用用于CRISPR/Cas9基因编辑的标准方案和方法将突变引入小鼠基因的外显子7中(Valenzuela等人,Nat Biotechnol.2003;21(6):652-9;Poueymirou等人,Nat Biotechnol.2007;25(1):91-9)。图4示出了靶向策略。将最终的靶向载体电穿孔到C57BL/6N小鼠胚胎干细胞中,并在插入下游内含子中的自缺失盒中经由潮霉素抗性进行选择。通过Sanger测序基因分型证实了携带所引入突变的小鼠。饲养靶向的缺失盒的敲入小鼠以获得所需的基因型。将杂合的敲入小鼠与129S6/SvEvTac野生型小鼠进行繁殖,以远交并产生混合背景系。具有这种杂交种遗传背景的杂合动物的交配能够产生存活至断奶后的有活力的纯合KI动物。
生长和骨骼表型分型。通过在指定的时间点记录体重来监测小鼠的生长动力学,并且通过双周成像进行总体骨骼表型分型,如先前所述进行体内μCT(Das NM,Hatsell S,Nannuru K,Huang L,Wen X,Wang L,Wang LH,Idone V,Meganck JA,Murphy A,EconomidesA,Xie L.In Vivo Quantitative Microcomputed Tomographic Analysis ofVasculature and Organs in a Normal and Diseased Mouse Model.PLoS One.2016;11(2):e0150085)。简言之,使用高速体内μCT扫描仪(Quantum FX,PerkinElmer,Hopkinton,MA,USA)进行全身μCT成像。将X射线源设置为88μA的电流和90kV的电压。经由在Quantum FX系统内的现有软件3D Viewer可视化CT成像。视场(FOV)为60,并且体素大小为240μm。在扫描期间将小鼠保持麻醉。具体地,通过将小鼠保持在2.5-3%的异氟烷中并以1.5升/分钟氧气流量进行2-3分钟来诱导麻醉,然后将所述小鼠放置在扫描平台上。通过连接至扫描平台的鼻锥实现了异氟烷的持续输送。在扫描过程之后,在加热灯下使小鼠复活并将其放回笼子。
使用Analyze软件包(AnalyzeDirect,Overland Park,KS,USA)从μCT扫描的图像数据计算出骨矿物质密度(BMD)和骨矿物质含量(BMC)。在扫描之后,进行图像处理步骤。使用Analyze软件包(AnalyzeDirect,Overland Park,KS,USA)内的容量编辑(Volume Edit)工具半自动地执行图像分割。简言之,使用半自动和手动技术(对象提取、区域增长和阈值工具)的组合来创建分割蒙版(对象图)。然后根据需要手动修改这些分割结果,并使用ROI工具进行定量。
结果-纯合(Col27a1G682R/G682R)KI小鼠在P7之前显示出严重的致死性,只有几只幼仔在断奶后存活。在E18.5时对纯合KI胚胎的表型分型显示异常的头骨形状、缩短的吻部,但在此阶段胚胎大小或长度没有显著差异。此外,纯合KI小鼠的肺部异常,气隙发育不良,并且间充质增厚。四只纯合KI小鼠存活至断奶后,并经历了总体表型和骨骼变化的进一步评价。
进行了杂合(Col27a1G682R/+)和纯合(Col27a1G682R/G682R)KI小鼠和野生型同窝幼仔的计算机断层扫描(μCT)全身扫描,以评价总体骨骼异常和作为人类患者中观察到的身材矮小表型替代物的减少长度。测量吻部至尾部基部(在尾椎4(CA4)处)的距离,以评价杂合型、纯合型和野生型小鼠之间的长度差异。纯合的突变型小鼠显示出明显的严重侏儒症,并且与野生型或杂合的同窝幼仔相比显著更小(图2A)。总身长显著减少(图2B、2D),并且所有长骨都更短。纯合的KI小鼠还呈现出明显的颅面异常,包括较短的吻部和略呈圆形的圆顶形状头骨,也可在胚胎早期观察到。对脊柱的分析证明,在所有评价的纯合KI小鼠中在3周龄时出现严重的胸椎后凸,这导致头骨与颈椎骨之间形成锐角,从而导致肋架向内弯曲。骨骼参数的分析揭示,如与杂合的KI和野生型小鼠相比,纯合的突变型小鼠显示出较低的骨矿物质含量(BMC)(图2C)。纯合小鼠的体重是野生型同窝幼仔的一半,并且在整个6个月的监测期内纯合小鼠的生长曲线仍然显著低于野生型和杂合的同窝幼仔。杂合小鼠是有活力的,并且没有显示出任何总体骨骼异常;骨骼参数与野生型同窝幼仔没有区别。在6个月时期内监测纯合和杂合的KI小鼠;衰老不会导致杂合小鼠在以后的年龄发生总体或可检测的骨骼异常。
进行对杂合(Col27a1G682R/+)和纯合(Col27a1G682R/G682R)KI小鼠和野生型同窝幼仔的组织学分析,以评价生长板缺陷。收集、固定和切片来自杂合(Col27a1G682R/+)和纯合(Col27a1G682R/G682R)KI小鼠和野生型同窝幼仔在P1时的长骨(股骨和胫骨)。然后根据标准方案对切片进行苏木精和伊红(H&E)、番红精或von Kossa染色。纯合KI小鼠的股骨和胫骨生长板的染色切片显示出增生区正常结构的完全丧失、柱状软骨细胞的不存在和破坏(图3)。番红精和von-Kossa染色剂的组织化学比较显示,与纯合KI和野生型小鼠相比,在纯合KI小鼠中的蛋白聚糖积累和矿化没有明显差异(图3)。有趣的是,虽然杂合KI小鼠中长骨的长度和总体形态与野生型同窝幼仔没有差异,但是对这些小鼠中生长板的组织学分析揭示出一个中间表型,其中生长板的增生区的长度得以维持,但可以观察到在软骨细胞的柱状排列中的一些破坏(图3)。
序列表
<110> 再生元制药公司(Regeneron Pharmaceuticals, Inc.)
<120> 斯蒂尔综合征的啮齿动物模型
<130> 35992PCT (10433WO01)
<150> 16/002,233
<151> 2018-06-07
<160> 6
<170> PatentIn版本3.5
<210> 1
<211> 7818
<212> DNA
<213> 智人(Homo sapiens)
<400> 1
tctcctcccc caggccggcg gggaggcagc ttccaccgcc ctccgcgcgc cctcacccgg 60
ccttgctctg cctccgggga ccgccagcag cccgcctcca aaagtttgat catctctctc 120
tctctttttc ttgcttcttc ttcctttttg gtggaagcag aaaaggaccg aggcaggggc 180
gagcgcggcg cccggactcc tgggaccatg ggcctggcgc gggcgcccgc ggggccccag 240
ccgcgctgcc tgcctgctcg ggcgcccctg ggcgcggggc tgcgctgggg gcgcgggggc 300
cgcgcgctct aagccggcct ggcgcggcgg ggcggggggc tggcggcccc atggggcgcg 360
cccacacttg ccccccgggc tcgggagcat gaagtagggg cctgccatgg gagcgggatc 420
ggcgcggggg gcccgaggca cagcggcggc ggcggcggcg cgcggggggg ggtttctctt 480
ctcctggatc ttagtctcgt ttgcctgtca cctggcctcc acccaaggag ctcctgaaga 540
tgtggacatc ctccagcggc tgggcctcag ctggacgaag gccgggagcc ctgcaccccc 600
gggagtcatt cctttccagt cgggcttcat ctttacgcag cgggcccggc tccaggctcc 660
cacgggcacc gtcattcctg ccgccttggg cacagagctg gcactggtgc tgagcctctg 720
ctcccaccgg gtgaaccatg ccttcctctt cgctgtccgc agccagaaac gcaagctgca 780
gctgggcctg cagttcctcc ccggcaagac ggtcgtccac ctcgggtccc ggcgctcagt 840
ggccttcgac ctcgacatgc acgacgggcg ctggcaccac ctggccctcg agctccgagg 900
ccgcacagtc actctggtga ctgcctgcgg gcagcgccgg gtgcctgtcc tgctgccttt 960
ccacagggac cctgcactcg accctggggg ctccttcctc tttgggaaga tgaacccgca 1020
tgcagtccag tttgaaggtg ctctctgcca gttcagtatc taccctgtga cgcaggtcgc 1080
tcacaattac tgtacccacc tgaggaagca gtgtggacag gctgacacgt accagtcccc 1140
actgggacct ctcttctccc aagactctgg cagacctttt accttccagt ccgacctcgc 1200
cctgctaggc ctggagaact tgaccactgc cacaccagcc ctggggtcac tgccagcagg 1260
caggggaccc agggggactg tggcacccgc cacgcccacc aagccccaaa ggactagccc 1320
cacaaaccct caccagcata tggcggtggg aggcccagcc caaaccccgc tgctacctgc 1380
caagctgtca gccagtaacg cacttgatcc catgctccca gcctctgttg gcggctctac 1440
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caaaagcctc cctaccaagc cttcggcccc ttctacttca attgtgccca tcaaaagccc 1560
ccatcctacc cagaaaacag ctccatcttc atttacaaag tcagccctac ccactcagaa 1620
gcaagtgcca cctacttccc gtccagttcc tgccagagtc tcccgtcccg cagagaagcc 1680
catccagagg aacccgggaa tgcccaggcc cccaccgccc agcacccggc ccctacctcc 1740
taccaccagc tcctctaaaa aacccattcc cacactagct cggactgagg ccaagataac 1800
cagccatgcc agtaagccgg cctctgcccg caccagcacc cacaaacctc ccccatttac 1860
tgctttatcc tcatctcctg cccctactcc tggttctacc aggagtactc ggccaccagc 1920
cacgatggta cctccaactt cgggcaccag cactcccaga acagcacctg ccgtccccac 1980
tcctggctca gctcccactg gaagcaagaa gcccattgga tcggaagcct caaagaaagc 2040
cggacccaag agcagccccc ggaagcctgt ccccctcaga cctgggaagg cagccaggga 2100
tgtccccttg agcgatctga caaccaggcc tagccccaga cagccccagc ccagtcagca 2160
gaccaccccg gccctggtat tggccccggc gcaattcctg tcctccagcc cccggcccac 2220
gagcagtggc tattcgatct tccacctggc aggatctacg cctttccctc tgctgatggg 2280
gcctccggga cccaagggag actgtggctt gccgggtccc cctgggctac ctgggctacc 2340
tggaatccct ggtgcacgtg ggcctcgggg tcctcctggg ccttatggaa atccaggtct 2400
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cggcctgcca gggtctgatg gagaacgagg cctgcctggc gttcctggca agaggggcaa 2760
gatgggtatg ccggggtttc ctggagtctt tggggaaaga ggccctcctg gactggatgg 2820
aaatcctgga gaactgggcc tgccaggccc ccctggagtc cccggcctca ttggtgactt 2880
aggagtgttg ggtccgattg gctacccggg acccaagggc atgaagggac tgatgggcag 2940
cgtgggggag cccggactga aaggtgataa gggtgaacaa ggggttccag gtgtgtcagg 3000
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ggggaagcca gggcctctgg gcaaagtcgg agacaaagga tccattgggt ttcccgggcc 3120
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catgaagggt aagcctggag cccgaggcct gccgggaccc cgtgggcagc tggggcccga 3240
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tcggccgggg cctgtgggag agcagggatt tatgggattc attggtctgg tcggggagcc 3420
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caaggggtcg atgggtcatc ctggaatgcc aggtggtatg gggacccctg gagagcctgg 3540
accccagggt cctccaggat ctcgaggccc accaggcatg aggggagcaa agggacgtcg 3600
gggcccccga ggaccggacg gaccagctgg ggagcaaggg tccaggggcc tgaagggccc 3660
tccaggaccc cagggcagac cgggccggcc tggacagcag ggtgtggctg gtgagcgagg 3720
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gatgggaccc aaggggccgc ctggtgcagt gggagaaccg ggccttcctg gggaagccgg 3900
gatgaagggt gaccttggac ccctgggcac tcctggggag cagggcctca ttgggcaacg 3960
gggagagcca ggccttgagg gtgacagtgg ccccatggga cctgatgggc tgaaggggga 4020
caggggagac ccagggcctg atggagaaca tggcgagaaa ggccaggaag ggctgatggg 4080
tgaggacggg ccccccggcc cccctggcgt cactggtgtc cggggtcctg aaggaaaatc 4140
agggaagcaa ggcgagaagg gccgcactgg agccaagggt gccaagggct atcaaggaca 4200
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aaaaggcgaa aagggggagc agggcgagga cggcaaggct gaggggcccc ctgggccacc 4440
tggagatcgg ggccctgtgg gtgatcgagg agaccgcggg gaaccgggag accctgggta 4500
ccctggacag gagggtgtgc aaggcctccg tggaaagcca ggccagcagg gccaacccgg 4560
gcatccggga ccccgggggt ggccgggacc caaaggatcg aaaggcgcag agggaccaaa 4620
gggaaagcaa ggcaaggcag gggccccagg ccggaggggg gtccagggcc tgcaggggct 4680
gccagggccc cggggcgtgg tggggagaca gggcctcgag ggcatcgctg gaccagatgg 4740
gcttcctggc agggacgggc aagcaggaca gcagggggag cagggagacg atggggaccc 4800
tggccccatg ggccctgctg ggaagagagg aaatccaggt gtggccggct tacctggagc 4860
acagggaccc ccaggattca agggtgagag tgggttaccc ggacagctgg gtccccctgg 4920
caagcgagga acagagggca gaacggggct ccctggaaac cagggggagc ctgggtccaa 4980
aggccagccg ggcgactctg gcgagatggg cttcccagga atggcaggtc tcttcggacc 5040
caagggcccg cctggagaca ttggcttcaa aggcatccag ggccctcggg ggccacctgg 5100
cttgatggga aaggaaggca tcgtcgggcc cctcggaatc ctgggacctt cgggactccc 5160
gggtccgaag ggtgacaaag gcagccgtgg ggactgggga ttgcaaggtc cgaggggtcc 5220
tcccggcccc agagggcggc ccggcccccc gggtcctcca gggggtccta tccaattgca 5280
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ccccgcccgg gtctgcaggg acctcatgga ctgtgagcag aagatggtgg atggtaccta 5520
ctgggtggat ccaaaccttg gctgctcctc tgacaccatc gaggtctcct gcaacttcac 5580
tcatggtgga cagacgtgtc tcaagcccat cacggcctcc aaggtcgagt ttgccatcag 5640
ccgggtccag atgaatttcc tgcacctgct aagctccgag gtgacccagc acatcaccat 5700
ccactgcctt aacatgaccg tgtggcagga gggcactggg cagaccccag ccaagcaggc 5760
cgtacgcttc cgggcctgga atggacagat ttttgaagct gggggtcagt tccggcccga 5820
ggtgtccatg gatggctgca aggtccaaga tggccgctgg catcagacac tcttcacctt 5880
ccggacccaa gacccccaac agctgcccat catcagtgtg gacaacctcc ctcctgcctc 5940
atcagggaag cagtaccgcc tggaagttgg acctgcgtgc ttcctctgac ctctgacctc 6000
gtggccactc taggcctcac ggaggaggga agaggaagag gcaaggggag ggtactgagg 6060
ggcagatggc tccaggagag gcagctcccc tgcccaaggg tccttgggca gaccccagct 6120
gttgtctgcc cagtagaagt gggtgggggt aggaggggat agggtgtcct tgggaacaat 6180
ggatcccagc ttagccccaa agaccaacca aagagccagc cagagtaagc tggacctgca 6240
acctgcctga gccccgtggc ctctcagctc tgcggccacc ccgttccctc cccagcttcc 6300
tgcccaaaga gccccacatt caagccaact tgagggaagg gggcgtctcg tcagctggtc 6360
cctgctaggg agctattgat gtgcaatatt agaaaggaga catgaaaaaa ggagaaaagg 6420
aaagacagaa gtgtatatat atattattta aacaaacaaa aagaaggtgc gttactattt 6480
ttttttcacc cgggaaagag gtgagaggat gggaaggagc agccaggcgt gggaagcggc 6540
gagatcctcg ggctgggggt gcccacgttt gctacctccc actgtgaaat cgctggtgct 6600
cacaattgtc tctcacagtg tatgtgattt ttttaaggaa aaaaaaaaat ccctatttaa 6660
gattctgaag gtgctaccat tattttgcca cagactttga agaaactttt ggatgtgggg 6720
catcatccgc atctttctct ctcctccaaa tgacaaagtt tggggaattt ttgaattttc 6780
ctagcatcgc ccttgtgctc atcaggtaat ctgctaagga ggaaaaaaga aaagaaaaaa 6840
ggaaaaaaaa aaaaaaaaag caaaacaaaa acaaaaacaa aaaccctacc agaaaccaga 6900
agtagagaga tttaccatat aacttatgga ctttgaaatg tctgtccttt taaggcagca 6960
gggaggcctg ggtgcgaagc atgttggctt ggcccttcac ggtcctggag ggaggtgagg 7020
ctggccttgg aaggcgtgcc ctggagaggt cttgggtgaa aacttgacct tgaagaaacc 7080
aatcacaaaa gcggcgttgg gtcagggcta ggcttagagg tgaagcatca acatggaacc 7140
atctcaggaa gccgcatcgc ctcttccgag gtcctcactt ccaggagcct gtccttgcaa 7200
gatgcaatca tcgttcctgc tttttcattg tcattaaatt ctgtagaaac ccattgtcat 7260
tagctccaag tgtaaatttg ggtcaaggag acagaataat aatgggaatc tcggagttcg 7320
acaccatagt gacgttcagc gtcctctgaa ttgtgctaca tcagcgaaca agtcggcgct 7380
tgaattggat tttgaggtta ttttaaccat ggaattattt ttatagaagg ggaaaatgta 7440
tgtgaaagtc tctatttgtg tatttctctc ctaaagttgt gtctctttgg gaattggatt 7500
tgatttttat tatttaatac ctcactttgg cccgtccccc ctcccaacac ttctgtatcc 7560
tcgccctgcc gccccagcct ggacgctctg cgtggaagtg cgtgtttgta gcagctcggg 7620
cctcatctca gcgctcggat ccctcctgct gccagaatcc actggcctct gtctcattct 7680
tgggttttcc tgctgtcttc gtttacgtct ctgtccacat gtcagtgtat taaaacccca 7740
atgggttccg tttctccttt tcccctctgg attttaaata aatatttaaa actgaggcaa 7800
tggaatgaca aaaaaaaa 7818
<210> 2
<211> 1860
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Met Gly Ala Gly Ser Ala Arg Gly Ala Arg Gly Thr Ala Ala Ala Ala
1 5 10 15
Ala Ala Arg Gly Gly Gly Phe Leu Phe Ser Trp Ile Leu Val Ser Phe
20 25 30
Ala Cys His Leu Ala Ser Thr Gln Gly Ala Pro Glu Asp Val Asp Ile
35 40 45
Leu Gln Arg Leu Gly Leu Ser Trp Thr Lys Ala Gly Ser Pro Ala Pro
50 55 60
Pro Gly Val Ile Pro Phe Gln Ser Gly Phe Ile Phe Thr Gln Arg Ala
65 70 75 80
Arg Leu Gln Ala Pro Thr Gly Thr Val Ile Pro Ala Ala Leu Gly Thr
85 90 95
Glu Leu Ala Leu Val Leu Ser Leu Cys Ser His Arg Val Asn His Ala
100 105 110
Phe Leu Phe Ala Val Arg Ser Gln Lys Arg Lys Leu Gln Leu Gly Leu
115 120 125
Gln Phe Leu Pro Gly Lys Thr Val Val His Leu Gly Ser Arg Arg Ser
130 135 140
Val Ala Phe Asp Leu Asp Met His Asp Gly Arg Trp His His Leu Ala
145 150 155 160
Leu Glu Leu Arg Gly Arg Thr Val Thr Leu Val Thr Ala Cys Gly Gln
165 170 175
Arg Arg Val Pro Val Leu Leu Pro Phe His Arg Asp Pro Ala Leu Asp
180 185 190
Pro Gly Gly Ser Phe Leu Phe Gly Lys Met Asn Pro His Ala Val Gln
195 200 205
Phe Glu Gly Ala Leu Cys Gln Phe Ser Ile Tyr Pro Val Thr Gln Val
210 215 220
Ala His Asn Tyr Cys Thr His Leu Arg Lys Gln Cys Gly Gln Ala Asp
225 230 235 240
Thr Tyr Gln Ser Pro Leu Gly Pro Leu Phe Ser Gln Asp Ser Gly Arg
245 250 255
Pro Phe Thr Phe Gln Ser Asp Leu Ala Leu Leu Gly Leu Glu Asn Leu
260 265 270
Thr Thr Ala Thr Pro Ala Leu Gly Ser Leu Pro Ala Gly Arg Gly Pro
275 280 285
Arg Gly Thr Val Ala Pro Ala Thr Pro Thr Lys Pro Gln Arg Thr Ser
290 295 300
Pro Thr Asn Pro His Gln His Met Ala Val Gly Gly Pro Ala Gln Thr
305 310 315 320
Pro Leu Leu Pro Ala Lys Leu Ser Ala Ser Asn Ala Leu Asp Pro Met
325 330 335
Leu Pro Ala Ser Val Gly Gly Ser Thr Arg Thr Pro Arg Pro Ala Ala
340 345 350
Ala Gln Pro Ser Gln Lys Ile Thr Ala Thr Lys Ile Pro Lys Ser Leu
355 360 365
Pro Thr Lys Pro Ser Ala Pro Ser Thr Ser Ile Val Pro Ile Lys Ser
370 375 380
Pro His Pro Thr Gln Lys Thr Ala Pro Ser Ser Phe Thr Lys Ser Ala
385 390 395 400
Leu Pro Thr Gln Lys Gln Val Pro Pro Thr Ser Arg Pro Val Pro Ala
405 410 415
Arg Val Ser Arg Pro Ala Glu Lys Pro Ile Gln Arg Asn Pro Gly Met
420 425 430
Pro Arg Pro Pro Pro Pro Ser Thr Arg Pro Leu Pro Pro Thr Thr Ser
435 440 445
Ser Ser Lys Lys Pro Ile Pro Thr Leu Ala Arg Thr Glu Ala Lys Ile
450 455 460
Thr Ser His Ala Ser Lys Pro Ala Ser Ala Arg Thr Ser Thr His Lys
465 470 475 480
Pro Pro Pro Phe Thr Ala Leu Ser Ser Ser Pro Ala Pro Thr Pro Gly
485 490 495
Ser Thr Arg Ser Thr Arg Pro Pro Ala Thr Met Val Pro Pro Thr Ser
500 505 510
Gly Thr Ser Thr Pro Arg Thr Ala Pro Ala Val Pro Thr Pro Gly Ser
515 520 525
Ala Pro Thr Gly Ser Lys Lys Pro Ile Gly Ser Glu Ala Ser Lys Lys
530 535 540
Ala Gly Pro Lys Ser Ser Pro Arg Lys Pro Val Pro Leu Arg Pro Gly
545 550 555 560
Lys Ala Ala Arg Asp Val Pro Leu Ser Asp Leu Thr Thr Arg Pro Ser
565 570 575
Pro Arg Gln Pro Gln Pro Ser Gln Gln Thr Thr Pro Ala Leu Val Leu
580 585 590
Ala Pro Ala Gln Phe Leu Ser Ser Ser Pro Arg Pro Thr Ser Ser Gly
595 600 605
Tyr Ser Ile Phe His Leu Ala Gly Ser Thr Pro Phe Pro Leu Leu Met
610 615 620
Gly Pro Pro Gly Pro Lys Gly Asp Cys Gly Leu Pro Gly Pro Pro Gly
625 630 635 640
Leu Pro Gly Leu Pro Gly Ile Pro Gly Ala Arg Gly Pro Arg Gly Pro
645 650 655
Pro Gly Pro Tyr Gly Asn Pro Gly Leu Pro Gly Pro Pro Gly Ala Lys
660 665 670
Gly Gln Lys Gly Asp Pro Gly Leu Ser Pro Gly Lys Ala His Asp Gly
675 680 685
Ala Lys Gly Asp Met Gly Leu Pro Gly Leu Ser Gly Asn Pro Gly Pro
690 695 700
Pro Gly Arg Lys Gly His Lys Gly Tyr Pro Gly Pro Ala Gly His Pro
705 710 715 720
Gly Glu Gln Gly Gln Pro Gly Pro Glu Gly Ser Pro Gly Ala Lys Gly
725 730 735
Tyr Pro Gly Arg Gln Gly Leu Pro Gly Pro Val Gly Asp Pro Gly Pro
740 745 750
Lys Gly Ser Arg Gly Tyr Ile Gly Leu Pro Gly Leu Phe Gly Leu Pro
755 760 765
Gly Ser Asp Gly Glu Arg Gly Leu Pro Gly Val Pro Gly Lys Arg Gly
770 775 780
Lys Met Gly Met Pro Gly Phe Pro Gly Val Phe Gly Glu Arg Gly Pro
785 790 795 800
Pro Gly Leu Asp Gly Asn Pro Gly Glu Leu Gly Leu Pro Gly Pro Pro
805 810 815
Gly Val Pro Gly Leu Ile Gly Asp Leu Gly Val Leu Gly Pro Ile Gly
820 825 830
Tyr Pro Gly Pro Lys Gly Met Lys Gly Leu Met Gly Ser Val Gly Glu
835 840 845
Pro Gly Leu Lys Gly Asp Lys Gly Glu Gln Gly Val Pro Gly Val Ser
850 855 860
Gly Asp Pro Gly Phe Gln Gly Asp Lys Gly Ser Gln Gly Leu Pro Gly
865 870 875 880
Phe Pro Gly Ala Arg Gly Lys Pro Gly Pro Leu Gly Lys Val Gly Asp
885 890 895
Lys Gly Ser Ile Gly Phe Pro Gly Pro Pro Gly Pro Glu Gly Phe Pro
900 905 910
Gly Asp Ile Gly Pro Pro Gly Asp Asn Gly Pro Glu Gly Met Lys Gly
915 920 925
Lys Pro Gly Ala Arg Gly Leu Pro Gly Pro Arg Gly Gln Leu Gly Pro
930 935 940
Glu Gly Asp Glu Gly Pro Met Gly Pro Pro Gly Ala Pro Gly Leu Glu
945 950 955 960
Gly Gln Pro Gly Arg Lys Gly Phe Pro Gly Arg Pro Gly Leu Asp Gly
965 970 975
Val Lys Gly Glu Pro Gly Asp Pro Gly Arg Pro Gly Pro Val Gly Glu
980 985 990
Gln Gly Phe Met Gly Phe Ile Gly Leu Val Gly Glu Pro Gly Ile Val
995 1000 1005
Gly Glu Lys Gly Asp Arg Gly Met Met Gly Pro Pro Gly Val Pro
1010 1015 1020
Gly Pro Lys Gly Ser Met Gly His Pro Gly Met Pro Gly Gly Met
1025 1030 1035
Gly Thr Pro Gly Glu Pro Gly Pro Gln Gly Pro Pro Gly Ser Arg
1040 1045 1050
Gly Pro Pro Gly Met Arg Gly Ala Lys Gly Arg Arg Gly Pro Arg
1055 1060 1065
Gly Pro Asp Gly Pro Ala Gly Glu Gln Gly Ser Arg Gly Leu Lys
1070 1075 1080
Gly Pro Pro Gly Pro Gln Gly Arg Pro Gly Arg Pro Gly Gln Gln
1085 1090 1095
Gly Val Ala Gly Glu Arg Gly His Leu Gly Ser Arg Gly Phe Pro
1100 1105 1110
Gly Ile Pro Gly Pro Ser Gly Pro Pro Gly Thr Lys Gly Leu Pro
1115 1120 1125
Gly Glu Pro Gly Pro Gln Gly Pro Gln Gly Pro Ile Gly Pro Pro
1130 1135 1140
Gly Glu Met Gly Pro Lys Gly Pro Pro Gly Ala Val Gly Glu Pro
1145 1150 1155
Gly Leu Pro Gly Glu Ala Gly Met Lys Gly Asp Leu Gly Pro Leu
1160 1165 1170
Gly Thr Pro Gly Glu Gln Gly Leu Ile Gly Gln Arg Gly Glu Pro
1175 1180 1185
Gly Leu Glu Gly Asp Ser Gly Pro Met Gly Pro Asp Gly Leu Lys
1190 1195 1200
Gly Asp Arg Gly Asp Pro Gly Pro Asp Gly Glu His Gly Glu Lys
1205 1210 1215
Gly Gln Glu Gly Leu Met Gly Glu Asp Gly Pro Pro Gly Pro Pro
1220 1225 1230
Gly Val Thr Gly Val Arg Gly Pro Glu Gly Lys Ser Gly Lys Gln
1235 1240 1245
Gly Glu Lys Gly Arg Thr Gly Ala Lys Gly Ala Lys Gly Tyr Gln
1250 1255 1260
Gly Gln Leu Gly Glu Met Gly Val Pro Gly Asp Pro Gly Pro Pro
1265 1270 1275
Gly Thr Pro Gly Pro Lys Gly Ser Arg Gly Ser Leu Gly Pro Thr
1280 1285 1290
Gly Ala Pro Gly Arg Met Gly Ala Gln Gly Glu Pro Gly Leu Ala
1295 1300 1305
Gly Tyr Asp Gly His Lys Gly Ile Val Gly Pro Leu Gly Pro Pro
1310 1315 1320
Gly Pro Lys Gly Glu Lys Gly Glu Gln Gly Glu Asp Gly Lys Ala
1325 1330 1335
Glu Gly Pro Pro Gly Pro Pro Gly Asp Arg Gly Pro Val Gly Asp
1340 1345 1350
Arg Gly Asp Arg Gly Glu Pro Gly Asp Pro Gly Tyr Pro Gly Gln
1355 1360 1365
Glu Gly Val Gln Gly Leu Arg Gly Lys Pro Gly Gln Gln Gly Gln
1370 1375 1380
Pro Gly His Pro Gly Pro Arg Gly Trp Pro Gly Pro Lys Gly Ser
1385 1390 1395
Lys Gly Ala Glu Gly Pro Lys Gly Lys Gln Gly Lys Ala Gly Ala
1400 1405 1410
Pro Gly Arg Arg Gly Val Gln Gly Leu Gln Gly Leu Pro Gly Pro
1415 1420 1425
Arg Gly Val Val Gly Arg Gln Gly Leu Glu Gly Ile Ala Gly Pro
1430 1435 1440
Asp Gly Leu Pro Gly Arg Asp Gly Gln Ala Gly Gln Gln Gly Glu
1445 1450 1455
Gln Gly Asp Asp Gly Asp Pro Gly Pro Met Gly Pro Ala Gly Lys
1460 1465 1470
Arg Gly Asn Pro Gly Val Ala Gly Leu Pro Gly Ala Gln Gly Pro
1475 1480 1485
Pro Gly Phe Lys Gly Glu Ser Gly Leu Pro Gly Gln Leu Gly Pro
1490 1495 1500
Pro Gly Lys Arg Gly Thr Glu Gly Arg Thr Gly Leu Pro Gly Asn
1505 1510 1515
Gln Gly Glu Pro Gly Ser Lys Gly Gln Pro Gly Asp Ser Gly Glu
1520 1525 1530
Met Gly Phe Pro Gly Met Ala Gly Leu Phe Gly Pro Lys Gly Pro
1535 1540 1545
Pro Gly Asp Ile Gly Phe Lys Gly Ile Gln Gly Pro Arg Gly Pro
1550 1555 1560
Pro Gly Leu Met Gly Lys Glu Gly Ile Val Gly Pro Leu Gly Ile
1565 1570 1575
Leu Gly Pro Ser Gly Leu Pro Gly Pro Lys Gly Asp Lys Gly Ser
1580 1585 1590
Arg Gly Asp Trp Gly Leu Gln Gly Pro Arg Gly Pro Pro Gly Pro
1595 1600 1605
Arg Gly Arg Pro Gly Pro Pro Gly Pro Pro Gly Gly Pro Ile Gln
1610 1615 1620
Leu Gln Gln Asp Asp Leu Gly Ala Ala Phe Gln Thr Trp Met Asp
1625 1630 1635
Thr Ser Gly Ala Leu Arg Pro Glu Ser Tyr Ser Tyr Pro Asp Arg
1640 1645 1650
Leu Val Leu Asp Gln Gly Gly Glu Ile Phe Lys Thr Leu His Tyr
1655 1660 1665
Leu Ser Asn Leu Ile Gln Ser Ile Lys Thr Pro Leu Gly Thr Lys
1670 1675 1680
Glu Asn Pro Ala Arg Val Cys Arg Asp Leu Met Asp Cys Glu Gln
1685 1690 1695
Lys Met Val Asp Gly Thr Tyr Trp Val Asp Pro Asn Leu Gly Cys
1700 1705 1710
Ser Ser Asp Thr Ile Glu Val Ser Cys Asn Phe Thr His Gly Gly
1715 1720 1725
Gln Thr Cys Leu Lys Pro Ile Thr Ala Ser Lys Val Glu Phe Ala
1730 1735 1740
Ile Ser Arg Val Gln Met Asn Phe Leu His Leu Leu Ser Ser Glu
1745 1750 1755
Val Thr Gln His Ile Thr Ile His Cys Leu Asn Met Thr Val Trp
1760 1765 1770
Gln Glu Gly Thr Gly Gln Thr Pro Ala Lys Gln Ala Val Arg Phe
1775 1780 1785
Arg Ala Trp Asn Gly Gln Ile Phe Glu Ala Gly Gly Gln Phe Arg
1790 1795 1800
Pro Glu Val Ser Met Asp Gly Cys Lys Val Gln Asp Gly Arg Trp
1805 1810 1815
His Gln Thr Leu Phe Thr Phe Arg Thr Gln Asp Pro Gln Gln Leu
1820 1825 1830
Pro Ile Ile Ser Val Asp Asn Leu Pro Pro Ala Ser Ser Gly Lys
1835 1840 1845
Gln Tyr Arg Leu Glu Val Gly Pro Ala Cys Phe Leu
1850 1855 1860
<210> 3
<211> 7635
<212> DNA
<213> 小家鼠(Mus musculus)
<400> 3
ccttttcctc tcctccccca ggccggcggg gaggcagctt ccaccgccct ccgcgcgcgc 60
tctcccggcc ttgctctgcc tccagagacc gctagcggcc cgcctccaaa agtttgatca 120
tctctctctc cctgcctttt cttgcttctt ccttttcggt ggaagcagaa aaagagcgag 180
gcaggggcga gcgcggctcc ggcagtcctg ggaccatggg cctggcgcgg gcgaccgccg 240
ggctggggcc gtgctgtccg tctgctccgg cgcccctggg cgcaggactg ggctgggggt 300
gcgccggcag cgcgctttga gccggcctgg cgcggcgcgg cggggggctg gcggccccat 360
ggggcgcgcc cacacttgcc ccccgggctc cgcagcatga agtaggggcc tgccatgggc 420
acgggattcg cgcggggggc ccgaggcaca gcggcgtcag gacccggggg ggggtttctc 480
ttcgcctgga tcttggtctc atttacctgt cacctggcct ccacccaagg agctcctgaa 540
gatgtggatg tcctccagcg gctgggcctc agctggacga aggccggggg tggccggagt 600
cctacacccc ctggtgtcat tcctttccca tctggcttca tcttcacaca gcgggccaag 660
ctgcaggccc ccacagccaa tgttcttccc accaccctgg ggcgggagct ggcattggtg 720
ttgagcctct gttcacatcg tgtgaaccat gccttcctct ttgccatccg cagcaggaaa 780
cacaagctgc aactgggtct gcagttcctc cccggcagga cgatcatcca cctggggcct 840
cggcaatcag tggccttcga cttggatgtg catgatgggc gctggcacca cctggcccta 900
gagttgcgtg gccgcacagt cacaatggtg acagcctgtg ggcagcacag ggtacctgtc 960
ccactgcctt cccgtaggga ctccatgctt gacccccagg gctcctttct cttggggaag 1020
gtgaaccccc gtgctgtcca gtttgaaggt gcactctgtc agttcagcat ccaccctgtg 1080
gcgcaggtcg ctcacaatta ctgtgcccac ctgagagagc ggtgccgaca ggtggacaca 1140
tatagtcccc aggtgggaac cctctttcct tgggactctg gcccagcctt tgctttgcat 1200
cctgaaccag ccttgcttgg cttggggaat ctgaccagaa ctccagcaac cctgggggcc 1260
aggcctgtaa gcagggcact tgcagtgact ctggctcctg ccatgcccac caagcccctg 1320
aggactgtcc acccagatgt ctctgaacac agctcttccc agaccccact gtcacctgcc 1380
aaacagtcgg ccaggaaaac accttccccc tcctcgtcag cttccctggc taattccacc 1440
agggtttatc gtccagctgc tgcccagcca agacagatca caactactag ccccaccaaa 1500
cgttccccca ccaagccttc tgtttctccc ctttcagtta cccccatgaa aagtccccat 1560
gcaacccaga aaacaggtgt cccttcattc acaaagcctg ttccacccac tcagaagcca 1620
gcgcccttca cctcctacct agcaccttcc aaagcctcta gtcccactgt gaggcctgtt 1680
cagaagactt tcatgacacc ccgacctcca gtccccagcc cccagcccct gcgccctact 1740
actggcttat ctaagaagtt cactaacccc actgttgcaa aatctaagtc caagacgacc 1800
agttgggcca gcaagccggt cttggcccgc tccagtgtcc ctaaaacgct tcagcaaact 1860
gttttgtccc agtctcctgt ttcctatctg ggctctcaga cactggctcc agccctccct 1920
cctttgggtg ttggaaatcc tagaacgatg cctcccacac gtgactctgc tttaactcct 1980
gctggaagca agaaattcac aggacgggaa acctccaaga aaaccagaca gaagagcagc 2040
ccccggaagc ccgaacctct cagccctggg aagtcagcca gggatgcctc accaagagac 2100
ctgacaacca agcctagccg gccgtccacc ccagccctgg tccttgcccc agcttacctc 2160
ctgtcctcca gcccccagcc caccagcagc agcttccctt tcttccacct gctgggccct 2220
acacctttcc cgatgctgat ggggcctcca ggctccaagg gagactgtgg cttgccgggt 2280
ccccctgggc ttccaggatt acctggatct ccgggcgcac gaggtcctcg gggtcctcct 2340
gggccgtacg ggaacccagg cccacctggc cctccaggag ccaaaggaca gaaaggggac 2400
ccaggactct caccaggaca ggctcacgat ggagcaaagg gcaacatggg cttgcctggg 2460
ctctccggaa atccaggacc cttgggaagg aagggacaca agggccatcc tggagcagca 2520
gggcaccctg gagaacaggg gcagccagga cctgagggca gtccaggggc caaaggttac 2580
cctggcaggc aggggttccc tggacctgta ggagaccctg gccccaaagg cagcaggggt 2640
tacattggtc ttccggggct ctttggcctg ccagggtcgg atggagagcg gggtctccct 2700
ggcgttcctg gcaagagggg cgagatgggt aggccgggct tccctggaga ctttggggaa 2760
agaggccccc ctggacttga tggcaaccct ggagaaattg gcctgccggg gccaccagga 2820
gtgctcgggc tcattggtga cacaggagca ctgggcccag ttggctaccc aggaccgaaa 2880
ggcatgaagg gactgatggg cggcgtgggg gagcccggac tgaaaggtga taagggtgaa 2940
caaggggtgc caggtgtgtc gggagatcct ggcttccaag gagacaaggg gagtcatggc 3000
ttgccagggc tcccgggtgg ccgggggaag ccagggcctc tgggaaaagc tggagacaaa 3060
ggatcacttg ggtttcctgg acctcctgga cctgagggtt tcccaggaga cattggccct 3120
ccaggggaca atggccctga aggcatgaag ggtaagcctg gagcccgagg cctgcctgga 3180
cctcctgggc agctggggcc tgagggagat gaaggaccca tggggccacc aggagtccca 3240
ggcttggagg gtcagcctgg aaggaaaggg tttcctggga ggcctggcct ggatggctcg 3300
aagggggaac caggggatcc tggacggcca ggacctgtgg gtgaacaggg gcttatggga 3360
ttcattggtc ttgtcggaga gcctggaatt gttggggaga agggagaccg tggggtgatg 3420
ggacccccag gtgcacctgg acccaagggg tcgatgggcc atcctggaac acccggtggt 3480
attgggaacc ctggagagcc tggaccctgg ggccctccag gatctcgagg cctgccaggc 3540
atgaggggag ccaaggggca ccggggccct cgaggacctg atggaccagc tggggagcag 3600
ggatccaagg gcctgaaggg tcgtgtagga cctcggggca gacctggcca gccaggacag 3660
cagggtgcag ctggtgagcg aggccactca ggtgcaaaag gcttccttgg catccctggt 3720
ccctcaggcc ctccaggtgc caagggcctc ccaggagaac cgggctctca gggacctcag 3780
gggccagttg gtcctccagg agaaatgggg cccaagggac cgccgggtgc agtgggagag 3840
cctggccttc ctggggactc cggaatgaag ggtgacctcg gacctctggg cccccctggg 3900
gagcaaggtc ttattgggca gcggggagag ccaggccttg agggagacca tggccctgtg 3960
gggccagatg ggctgaaggg cgacaggggc gacccagggc ccgatggcga gcatggtgaa 4020
aagggccagg aagggctgaa aggagaggat gggtcccctg ggcccccggg catcactggc 4080
gtcccgggtc gtgaggggaa gccgggcaag cagggtgaga aaggccagag gggagctaag 4140
ggtgccaagg gccaccaagg atatctggga gagatgggca tccccggaga acctgggccc 4200
cctgggaccc caggtcctaa agggtcccgg ggcaccctag gaccaacggg tgctccagga 4260
cggatgggag cccaaggaga accaggattg gccggttata atggacacaa aggcatcaca 4320
ggacccctcg ggcctcccgg gcccaaaggc gagaaggggg accagggcga ggatggcaag 4380
accgaggggc cccctgggcc accaggagat cggggtcctg tgggtgatcg aggagaccgt 4440
ggggagccag gcgaccctgg ataccctggt caagagggag ttcaaggcct ccgtggagaa 4500
ccgggccagc agggacagcc tgggcatcca ggaccccggg ggcgcccagg acccaaagga 4560
tcaaaaggcg aagagggccc aaagggaaag ccaggcaagg ctgggccatc aggccggagg 4620
gggacccagg gccttcaagg actgccaggc ccccgaggcg tggtggggag acagggccct 4680
gagggcactg ctggatctga tgggattcct ggcagagatg gtcggccagg atatcaggga 4740
gaccagggaa atgatgggga ccctggccct gtgggccctg ctgggagaag aggaaatcca 4800
ggtgtggctg gcttgcctgg agcacagggg cctccgggat tcaagggtga aagtgggtta 4860
cctgggcaac tgggtccccc tggaaaacga gggacagaag gtggaacagg gcttcctggg 4920
aaccaggggg agccaggatc caaaggccag ccgggtgact ctggcgagat gggcttccca 4980
ggagtggctg gcctctttgg acccaagggc ccccctggag acattggctt caaaggcatc 5040
caaggtcctc gggggcctcc tggcttgatg ggaaaggaag gtatcattgg cccccccgga 5100
atgctgggac cttctggact cccgggtccc aaaggtgaca gaggcagccg aggagacttg 5160
ggactgcaag gcccaagggg tcctcctggt ccaaggggcc ggccaggtcc cccgggccct 5220
ccttggcatc ccatccagtt tcagcaagat gaccttggag cagctttcca gacatggatg 5280
gatgctcaag gagccgtcag atcggagggg tacagctatc cggaccagct ggcgctagac 5340
cagggagggg agatcttcaa aaccttacac tacctcagca acctcatcca gagcattaag 5400
acacccttgg gcaccaagga gaacccagcc cgggtctgcc gggacctcat ggactgtgag 5460
cagaggatgg cggatggtac ctactgggtg gaccccaacc tcggctgctc ctctgacacc 5520
attgaagtct cctgcaactt tacacagggt gggcagacgt gcctgaagcc catcacggcc 5580
tccaaggccg agtttgctgt gagtcgggtc cagatgaatt tcttgcacct gctgagctct 5640
gaggggacac agcatatcac aatccactgt ctgaacatga cggtgtggca ggagggaccg 5700
ggacgctcct ctgccagaca ggctgtgcgc ttccgtgcct ggaacggaca ggtcttcgaa 5760
gctgggggtc agttcaggcc agaggtgtct atggatggct gcaaggtcca tgatggccgc 5820
tggcatcaga cactgttcac cttccggacc caggaccccc agcagctgcc catcgtcagt 5880
gtggacaatc tcccgcctgt ctcatcaggg aagcagtacc gcctggaagt tggacctgcg 5940
tgcttcctct gacctctgac ctctaggctc atctaagcct tgtggggaaa gggaagagat 6000
ggggacagct ggtcccagga gatgcaggcc cttgccttag gatcctggtg caggtcctag 6060
ttgttatctg ctcagccgga gttgagaagg agtaacaggt ctgaggctgt cccggagaac 6120
cacccatccc agctcagccc caagaaccaa ccaaagagcc agtcaaaagc aagctgggtt 6180
tgcagcccac tccagcccat ggcctgttgc ccagctctgt agacatccct gctccccagc 6240
tgcccaaaga ccccctcccc attgatgcca cctcaaggaa agggggcatg ttgccagctg 6300
gttcccgcta gggagctttc gatgtgcaat attagaaagg agacatggaa aaaaaaagag 6360
gaggaaaagg aaagaaatct atatatatta tttaaacaaa gagaaggtgt gttactattt 6420
ttttcacttg ggagaggtga ggaagagcaa gagaagctgg gggtgtggag aggcaggtcc 6480
cccaggctgg gatgctggcc cctagactag ggtgctgacc cctgggctgg ggtgctgtgt 6540
gctacctccc actgtgaaat cgctggtgct cacaattgtc tcttgtaatg tatgtgattt 6600
ttttaaggag aaaaagaaac ttatttaaga ttctgaaggt gctactattt tctgttgcca 6660
caggctttaa agaaactttc tgaatggggc ctggcccact tctctttctc tcctccaaat 6720
gaggagttaa aaatgttact agcatagccc acccgtgtaa tccgttgaaa aggaacaaaa 6780
ggaaaaaaga aaagaaagaa aagaaaaaaa aagaaaaaga aaaaacaaaa caaaacaaaa 6840
aaatcctcct agaaaccaga agtagagaga tttctgctaa ttctgggctt tgaagcgtac 6900
gtcttttgag ggggcatttt gatgtggtcc tccttgcttc tggagggact tggttccctt 6960
tagaaaacct gccctgggaa aagacttctt ggttttgagg aagatccttg gttagcgatg 7020
atcttggagg tggactaagt ccagagccat ccctgaagcc aggtgactgt cccaaggtct 7080
tccctcccgg gagcccaacc tttcgagtgc agccaaacct tactgctttt acaacattgc 7140
acagctgtgt agaaaccccg tgttctttcc cataggtgcc aatttgggtg ggggaggaag 7200
gaacaattac aagatcccca tctgtctgcc catgccacct aaacaagtca ggactccaat 7260
tggattttga agttatttta attatagaat tattttttta gaagaaagat ggatgtgata 7320
gtctatattt gtgtgtttct aaagttgtgt cttgtggggg aattggattc cattttagtt 7380
atttaatacc tcactcccac ccacctgcat actgcttgtg tgtcccggcc tgtcccgcaa 7440
gcctagttgt gctttttgtt gtctgttccc cgtgccccct cctgtgtctc actctgtctt 7500
cttgtcactt gatgtgcatt tgctgttgtt ctttcgtttc tgtctaaatg tcagtgtgtt 7560
caaaccccca gagggttctg tttttcccat tcccttctgg actttaaata aatatttaaa 7620
actgagcaat ggaaa 7635
<210> 4
<211> 1845
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 4
Met Gly Thr Gly Phe Ala Arg Gly Ala Arg Gly Thr Ala Ala Ser Gly
1 5 10 15
Pro Gly Gly Gly Phe Leu Phe Ala Trp Ile Leu Val Ser Phe Thr Cys
20 25 30
His Leu Ala Ser Thr Gln Gly Ala Pro Glu Asp Val Asp Val Leu Gln
35 40 45
Arg Leu Gly Leu Ser Trp Thr Lys Ala Gly Gly Gly Arg Ser Pro Thr
50 55 60
Pro Pro Gly Val Ile Pro Phe Pro Ser Gly Phe Ile Phe Thr Gln Arg
65 70 75 80
Ala Lys Leu Gln Ala Pro Thr Ala Asn Val Leu Pro Thr Thr Leu Gly
85 90 95
Arg Glu Leu Ala Leu Val Leu Ser Leu Cys Ser His Arg Val Asn His
100 105 110
Ala Phe Leu Phe Ala Ile Arg Ser Arg Lys His Lys Leu Gln Leu Gly
115 120 125
Leu Gln Phe Leu Pro Gly Arg Thr Ile Ile His Leu Gly Pro Arg Gln
130 135 140
Ser Val Ala Phe Asp Leu Asp Val His Asp Gly Arg Trp His His Leu
145 150 155 160
Ala Leu Glu Leu Arg Gly Arg Thr Val Thr Met Val Thr Ala Cys Gly
165 170 175
Gln His Arg Val Pro Val Pro Leu Pro Ser Arg Arg Asp Ser Met Leu
180 185 190
Asp Pro Gln Gly Ser Phe Leu Leu Gly Lys Val Asn Pro Arg Ala Val
195 200 205
Gln Phe Glu Gly Ala Leu Cys Gln Phe Ser Ile His Pro Val Ala Gln
210 215 220
Val Ala His Asn Tyr Cys Ala His Leu Arg Glu Arg Cys Arg Gln Val
225 230 235 240
Asp Thr Tyr Ser Pro Gln Val Gly Thr Leu Phe Pro Trp Asp Ser Gly
245 250 255
Pro Ala Phe Ala Leu His Pro Glu Pro Ala Leu Leu Gly Leu Gly Asn
260 265 270
Leu Thr Arg Thr Pro Ala Thr Leu Gly Ala Arg Pro Val Ser Arg Ala
275 280 285
Leu Ala Val Thr Leu Ala Pro Ala Met Pro Thr Lys Pro Leu Arg Thr
290 295 300
Val His Pro Asp Val Ser Glu His Ser Ser Ser Gln Thr Pro Leu Ser
305 310 315 320
Pro Ala Lys Gln Ser Ala Arg Lys Thr Pro Ser Pro Ser Ser Ser Ala
325 330 335
Ser Leu Ala Asn Ser Thr Arg Val Tyr Arg Pro Ala Ala Ala Gln Pro
340 345 350
Arg Gln Ile Thr Thr Thr Ser Pro Thr Lys Arg Ser Pro Thr Lys Pro
355 360 365
Ser Val Ser Pro Leu Ser Val Thr Pro Met Lys Ser Pro His Ala Thr
370 375 380
Gln Lys Thr Gly Val Pro Ser Phe Thr Lys Pro Val Pro Pro Thr Gln
385 390 395 400
Lys Pro Ala Pro Phe Thr Ser Tyr Leu Ala Pro Ser Lys Ala Ser Ser
405 410 415
Pro Thr Val Arg Pro Val Gln Lys Thr Phe Met Thr Pro Arg Pro Pro
420 425 430
Val Pro Ser Pro Gln Pro Leu Arg Pro Thr Thr Gly Leu Ser Lys Lys
435 440 445
Phe Thr Asn Pro Thr Val Ala Lys Ser Lys Ser Lys Thr Thr Ser Trp
450 455 460
Ala Ser Lys Pro Val Leu Ala Arg Ser Ser Val Pro Lys Thr Leu Gln
465 470 475 480
Gln Thr Val Leu Ser Gln Ser Pro Val Ser Tyr Leu Gly Ser Gln Thr
485 490 495
Leu Ala Pro Ala Leu Pro Pro Leu Gly Val Gly Asn Pro Arg Thr Met
500 505 510
Pro Pro Thr Arg Asp Ser Ala Leu Thr Pro Ala Gly Ser Lys Lys Phe
515 520 525
Thr Gly Arg Glu Thr Ser Lys Lys Thr Arg Gln Lys Ser Ser Pro Arg
530 535 540
Lys Pro Glu Pro Leu Ser Pro Gly Lys Ser Ala Arg Asp Ala Ser Pro
545 550 555 560
Arg Asp Leu Thr Thr Lys Pro Ser Arg Pro Ser Thr Pro Ala Leu Val
565 570 575
Leu Ala Pro Ala Tyr Leu Leu Ser Ser Ser Pro Gln Pro Thr Ser Ser
580 585 590
Ser Phe Pro Phe Phe His Leu Leu Gly Pro Thr Pro Phe Pro Met Leu
595 600 605
Met Gly Pro Pro Gly Ser Lys Gly Asp Cys Gly Leu Pro Gly Pro Pro
610 615 620
Gly Leu Pro Gly Leu Pro Gly Ser Pro Gly Ala Arg Gly Pro Arg Gly
625 630 635 640
Pro Pro Gly Pro Tyr Gly Asn Pro Gly Pro Pro Gly Pro Pro Gly Ala
645 650 655
Lys Gly Gln Lys Gly Asp Pro Gly Leu Ser Pro Gly Gln Ala His Asp
660 665 670
Gly Ala Lys Gly Asn Met Gly Leu Pro Gly Leu Ser Gly Asn Pro Gly
675 680 685
Pro Leu Gly Arg Lys Gly His Lys Gly His Pro Gly Ala Ala Gly His
690 695 700
Pro Gly Glu Gln Gly Gln Pro Gly Pro Glu Gly Ser Pro Gly Ala Lys
705 710 715 720
Gly Tyr Pro Gly Arg Gln Gly Phe Pro Gly Pro Val Gly Asp Pro Gly
725 730 735
Pro Lys Gly Ser Arg Gly Tyr Ile Gly Leu Pro Gly Leu Phe Gly Leu
740 745 750
Pro Gly Ser Asp Gly Glu Arg Gly Leu Pro Gly Val Pro Gly Lys Arg
755 760 765
Gly Glu Met Gly Arg Pro Gly Phe Pro Gly Asp Phe Gly Glu Arg Gly
770 775 780
Pro Pro Gly Leu Asp Gly Asn Pro Gly Glu Ile Gly Leu Pro Gly Pro
785 790 795 800
Pro Gly Val Leu Gly Leu Ile Gly Asp Thr Gly Ala Leu Gly Pro Val
805 810 815
Gly Tyr Pro Gly Pro Lys Gly Met Lys Gly Leu Met Gly Gly Val Gly
820 825 830
Glu Pro Gly Leu Lys Gly Asp Lys Gly Glu Gln Gly Val Pro Gly Val
835 840 845
Ser Gly Asp Pro Gly Phe Gln Gly Asp Lys Gly Ser His Gly Leu Pro
850 855 860
Gly Leu Pro Gly Gly Arg Gly Lys Pro Gly Pro Leu Gly Lys Ala Gly
865 870 875 880
Asp Lys Gly Ser Leu Gly Phe Pro Gly Pro Pro Gly Pro Glu Gly Phe
885 890 895
Pro Gly Asp Ile Gly Pro Pro Gly Asp Asn Gly Pro Glu Gly Met Lys
900 905 910
Gly Lys Pro Gly Ala Arg Gly Leu Pro Gly Pro Pro Gly Gln Leu Gly
915 920 925
Pro Glu Gly Asp Glu Gly Pro Met Gly Pro Pro Gly Val Pro Gly Leu
930 935 940
Glu Gly Gln Pro Gly Arg Lys Gly Phe Pro Gly Arg Pro Gly Leu Asp
945 950 955 960
Gly Ser Lys Gly Glu Pro Gly Asp Pro Gly Arg Pro Gly Pro Val Gly
965 970 975
Glu Gln Gly Leu Met Gly Phe Ile Gly Leu Val Gly Glu Pro Gly Ile
980 985 990
Val Gly Glu Lys Gly Asp Arg Gly Val Met Gly Pro Pro Gly Ala Pro
995 1000 1005
Gly Pro Lys Gly Ser Met Gly His Pro Gly Thr Pro Gly Gly Ile
1010 1015 1020
Gly Asn Pro Gly Glu Pro Gly Pro Trp Gly Pro Pro Gly Ser Arg
1025 1030 1035
Gly Leu Pro Gly Met Arg Gly Ala Lys Gly His Arg Gly Pro Arg
1040 1045 1050
Gly Pro Asp Gly Pro Ala Gly Glu Gln Gly Ser Lys Gly Leu Lys
1055 1060 1065
Gly Arg Val Gly Pro Arg Gly Arg Pro Gly Gln Pro Gly Gln Gln
1070 1075 1080
Gly Ala Ala Gly Glu Arg Gly His Ser Gly Ala Lys Gly Phe Leu
1085 1090 1095
Gly Ile Pro Gly Pro Ser Gly Pro Pro Gly Ala Lys Gly Leu Pro
1100 1105 1110
Gly Glu Pro Gly Ser Gln Gly Pro Gln Gly Pro Val Gly Pro Pro
1115 1120 1125
Gly Glu Met Gly Pro Lys Gly Pro Pro Gly Ala Val Gly Glu Pro
1130 1135 1140
Gly Leu Pro Gly Asp Ser Gly Met Lys Gly Asp Leu Gly Pro Leu
1145 1150 1155
Gly Pro Pro Gly Glu Gln Gly Leu Ile Gly Gln Arg Gly Glu Pro
1160 1165 1170
Gly Leu Glu Gly Asp His Gly Pro Val Gly Pro Asp Gly Leu Lys
1175 1180 1185
Gly Asp Arg Gly Asp Pro Gly Pro Asp Gly Glu His Gly Glu Lys
1190 1195 1200
Gly Gln Glu Gly Leu Lys Gly Glu Asp Gly Ser Pro Gly Pro Pro
1205 1210 1215
Gly Ile Thr Gly Val Pro Gly Arg Glu Gly Lys Pro Gly Lys Gln
1220 1225 1230
Gly Glu Lys Gly Gln Arg Gly Ala Lys Gly Ala Lys Gly His Gln
1235 1240 1245
Gly Tyr Leu Gly Glu Met Gly Ile Pro Gly Glu Pro Gly Pro Pro
1250 1255 1260
Gly Thr Pro Gly Pro Lys Gly Ser Arg Gly Thr Leu Gly Pro Thr
1265 1270 1275
Gly Ala Pro Gly Arg Met Gly Ala Gln Gly Glu Pro Gly Leu Ala
1280 1285 1290
Gly Tyr Asn Gly His Lys Gly Ile Thr Gly Pro Leu Gly Pro Pro
1295 1300 1305
Gly Pro Lys Gly Glu Lys Gly Asp Gln Gly Glu Asp Gly Lys Thr
1310 1315 1320
Glu Gly Pro Pro Gly Pro Pro Gly Asp Arg Gly Pro Val Gly Asp
1325 1330 1335
Arg Gly Asp Arg Gly Glu Pro Gly Asp Pro Gly Tyr Pro Gly Gln
1340 1345 1350
Glu Gly Val Gln Gly Leu Arg Gly Glu Pro Gly Gln Gln Gly Gln
1355 1360 1365
Pro Gly His Pro Gly Pro Arg Gly Arg Pro Gly Pro Lys Gly Ser
1370 1375 1380
Lys Gly Glu Glu Gly Pro Lys Gly Lys Pro Gly Lys Ala Gly Pro
1385 1390 1395
Ser Gly Arg Arg Gly Thr Gln Gly Leu Gln Gly Leu Pro Gly Pro
1400 1405 1410
Arg Gly Val Val Gly Arg Gln Gly Pro Glu Gly Thr Ala Gly Ser
1415 1420 1425
Asp Gly Ile Pro Gly Arg Asp Gly Arg Pro Gly Tyr Gln Gly Asp
1430 1435 1440
Gln Gly Asn Asp Gly Asp Pro Gly Pro Val Gly Pro Ala Gly Arg
1445 1450 1455
Arg Gly Asn Pro Gly Val Ala Gly Leu Pro Gly Ala Gln Gly Pro
1460 1465 1470
Pro Gly Phe Lys Gly Glu Ser Gly Leu Pro Gly Gln Leu Gly Pro
1475 1480 1485
Pro Gly Lys Arg Gly Thr Glu Gly Gly Thr Gly Leu Pro Gly Asn
1490 1495 1500
Gln Gly Glu Pro Gly Ser Lys Gly Gln Pro Gly Asp Ser Gly Glu
1505 1510 1515
Met Gly Phe Pro Gly Val Ala Gly Leu Phe Gly Pro Lys Gly Pro
1520 1525 1530
Pro Gly Asp Ile Gly Phe Lys Gly Ile Gln Gly Pro Arg Gly Pro
1535 1540 1545
Pro Gly Leu Met Gly Lys Glu Gly Ile Ile Gly Pro Pro Gly Met
1550 1555 1560
Leu Gly Pro Ser Gly Leu Pro Gly Pro Lys Gly Asp Arg Gly Ser
1565 1570 1575
Arg Gly Asp Leu Gly Leu Gln Gly Pro Arg Gly Pro Pro Gly Pro
1580 1585 1590
Arg Gly Arg Pro Gly Pro Pro Gly Pro Pro Trp His Pro Ile Gln
1595 1600 1605
Phe Gln Gln Asp Asp Leu Gly Ala Ala Phe Gln Thr Trp Met Asp
1610 1615 1620
Ala Gln Gly Ala Val Arg Ser Glu Gly Tyr Ser Tyr Pro Asp Gln
1625 1630 1635
Leu Ala Leu Asp Gln Gly Gly Glu Ile Phe Lys Thr Leu His Tyr
1640 1645 1650
Leu Ser Asn Leu Ile Gln Ser Ile Lys Thr Pro Leu Gly Thr Lys
1655 1660 1665
Glu Asn Pro Ala Arg Val Cys Arg Asp Leu Met Asp Cys Glu Gln
1670 1675 1680
Arg Met Ala Asp Gly Thr Tyr Trp Val Asp Pro Asn Leu Gly Cys
1685 1690 1695
Ser Ser Asp Thr Ile Glu Val Ser Cys Asn Phe Thr Gln Gly Gly
1700 1705 1710
Gln Thr Cys Leu Lys Pro Ile Thr Ala Ser Lys Ala Glu Phe Ala
1715 1720 1725
Val Ser Arg Val Gln Met Asn Phe Leu His Leu Leu Ser Ser Glu
1730 1735 1740
Gly Thr Gln His Ile Thr Ile His Cys Leu Asn Met Thr Val Trp
1745 1750 1755
Gln Glu Gly Pro Gly Arg Ser Ser Ala Arg Gln Ala Val Arg Phe
1760 1765 1770
Arg Ala Trp Asn Gly Gln Val Phe Glu Ala Gly Gly Gln Phe Arg
1775 1780 1785
Pro Glu Val Ser Met Asp Gly Cys Lys Val His Asp Gly Arg Trp
1790 1795 1800
His Gln Thr Leu Phe Thr Phe Arg Thr Gln Asp Pro Gln Gln Leu
1805 1810 1815
Pro Ile Val Ser Val Asp Asn Leu Pro Pro Val Ser Ser Gly Lys
1820 1825 1830
Gln Tyr Arg Leu Glu Val Gly Pro Ala Cys Phe Leu
1835 1840 1845
<210> 5
<211> 5568
<212> DNA
<213> 褐家鼠(Rattus norvegicus)
<400> 5
atgggcctgg cgcgggcgac cgcggggctg gggccgtgct gtccgcctgc tccggcgctc 60
ctgggcgcag ggctgcgctg ggggggattt ctcttcgcct ggatcttggt ctcattttcc 120
tgtcatctgg cctccaccca aggagctcct gaagatgtgg atgtcctcca gcggctgggc 180
ctcagctgga cgaaagctgg gggtggccgg agccccgcac cccctggtgt cattcctttc 240
ccatctggct tcatcttcac acagcgggcc aagctgcagg cccctactac caatgtcctt 300
cccaccaccc tggggcggga gctggcattg gtgttgagcc tctgttcgca ccgtgtgaac 360
catgccttcc tcttcgccat ccgcagcagg aaacacaggc tgcagctggg tctgcagttc 420
ctccccggca ggactctcgt ccacctggga cctcggcaat ctgtggcctt cgacttggat 480
gtgcatgatg ggcgctggca ccacctggcc ctagagttgc gtggtcgcac ggtcacattg 540
gtgacagcct gtgggcagca cagggtacct gttccgctgc cttcccgtag ggactccatg 600
cttgaccccc agggctcctt tctcttgggg aagatgaacc cccgagctgt ccagtttgaa 660
ggtgcactct gtcagttcag catccatccc gtggcgcagg tcgctcacaa ttactgtgcc 720
cacctgagag aacggtgccg acaggtggac acgtatggtc cccaggtggg agccctcttt 780
ccctgggact ctggcccagc ctttgctttg catcctgaac cagccttgct tggtctgggg 840
aacctgacca gaaacccagc aaccctaggg tccaggccta taagcagggg actcatggtg 900
actatggctc ctgccgtgcc caccaagccc ctaaggatgg tccaccaaga tgtctccaaa 960
ctcggctctt ctcagacccc attggtccct gccaaacagt cagccagaaa aacaccttcc 1020
cccttccctt cagctgctct ggctaattcc accagggttt ttcactcagc tcctgcccag 1080
ccacgacaaa tcacagctac tagccccacc aaacgtcccc cgaccaagcc ttctgtttct 1140
tccctttcag ttacccccat gaaaagtccc caggcaatcc agaaagcagg taccccttca 1200
ttctcaaggc ccattccaac cacccagaag ccaacacccc tcacctccca cccatcaccc 1260
tccaaagtct ctagtgccac tgtgaggcct gtccagaaga ctttcatgac accccaacct 1320
ccaaccctga gtccccaagc cctgcaccct attactggct tacctaagaa gttcactatc 1380
cccacagtag caaaacctca gtccaagatg accagttggg ccagcaagcc agtcttggcc 1440
cgcaccaatg tccctaaggc tcttgagcaa actgttgtgg cccagtcctc tgtttcctat 1500
ctgggctctc agacactggc tacagccctc cctcctctgg gtgttggaaa ttctagaatg 1560
atgccttcca cacgtgactc tacttcaact cctgctggaa gcaagaaaat cacaggattg 1620
gaagcttcca agaaaaccag acataagagc agcccccgga agcccatacc tctcagctct 1680
gggaagacag ccagggatgc ttcaccaaga gacctgacaa ccaagcctag ccagctgtcc 1740
actccagccc tggtccttgc cccagcccac ctcctgtcct ccagccccca gcccaccagc 1800
agcagctttt ctttcttcca cctgccggaa cctacacctt tcctgatgct gatggggcct 1860
cctggctcca agggagactg tggcttgccg ggccctcctg ggcttccagg attacctgga 1920
tctccgggtc cacgaggtcc tcggggtcct cctgggccat ttgggaaccc aggtctacct 1980
ggacctcctg gagccaaagg acagaaaggg gacccgggac tctcaccagg acaggctcac 2040
gatggggcaa agggcaacat gggcttgcct gggctcgccg gaaatccagg acccatggga 2100
cggaagggac acaagggcca ccctggagcg gcagggcacc ctggagaaca ggggcagcca 2160
ggacctgagg gcagtccagg ggccaaaggt taccctggca ggcaggggtt ccctggacct 2220
gtaggagacc ctggccccaa aggcagcagg ggttacattg ggcttccggg gctctttggc 2280
ctgccagggt cggatggaga gcggggtctc cccggcattc ctggcaagag gggcgagatg 2340
ggtaggccgg gcttccctgg agactttggg gaaagaggtc cccctggact tgatgggaac 2400
cctggggaaa ttggcctgcc aggaccacca ggagtgctcg ggctccttgg tgacatggga 2460
gcattaggtc cagttggcta cccgggacca aaaggcatga agggactgat gggcggcgtg 2520
ggggagcccg gactgaaagg tgataagggt gaacaagggg tgccaggtgt atcgggagat 2580
cctggcttcc aaggagacaa ggggagtcat ggcttgccag ggttcccagg tgcccggggg 2640
aagccagggc ctatgggcaa agctggggac aaaggctcac ttgggcttcc tggacctcct 2700
ggtcctgagg gtttcccagg agacattggc cccccagggg acaatggccc tgaaggcatg 2760
aagggtaagc ctggagcccg aggcctacct ggacctcctg ggcagctggg gcctgaggga 2820
gatgaaggac ccatggggcc accaggagtc ccaggcttgg agggtcaacc tggaaggaag 2880
gggttcccgg ggaggcctgg cctggacggc tcgaaggggg aaccagggga tcctggacgg 2940
ccagggcctg tgggtgaaca ggggcttatg ggatttgttg gtctggttgg agagcctgga 3000
attgttgggg agaagggaga ccgtggagtg atgggacccc caggggcacc tggacccaag 3060
gggtcgatgg gccatcctgg aacacctggt ggtgttgggg accctggaga gcctggaccc 3120
tggggccctc caggatctcg aggactgcca ggcatgaggg gagccaaggg gcaccggggc 3180
cctcgaggac ctgatggacc agctggggag caggggtcca agggcctgaa gggtcgtgta 3240
gggcctcggg gcagacctgg ccagccagga cagcagggtg cagctggcga gcgaggccac 3300
tcaggtgcaa aaggcttcct tggcattcct ggtccctcag gccctccagg tgccaagggc 3360
ctcccaggag aaccgggctc tcagggacct caggggccag ttggtcctcc aggagagatg 3420
ggacccaagg ggccgcctgg tgcagtggga gaacctggcc ttcctgggga ctccggtatg 3480
aagggtgacc ttggacctct gggccctcct ggggaacaag ggctcattgg gcaacgggga 3540
gagccaggcc tcgagggaga ccttggccca gtggggccag atgggctgaa gggggacagg 3600
ggtgacccag gtcctgatgg tgaacatggt gaaaagggtc aggaaggact gaaaggagag 3660
gaggggctcc ctgggccccc aggcatcact ggtgtccggg gtcgtgaagg gaagcctggc 3720
agtcagggtg agaagggcca gaggggagct aagggtgcca agggctacca aggacagctg 3780
ggagagatgg gcatccctgg agaccctggc ccccctggca ccccaggtcc taaagggtcc 3840
cggggcaccc taggaccaat gggtgctcca ggacggatgg gagcccaagg agaaccagga 3900
ttggctggtt ataatgggca taaaggcatc acgggacctc tcgggcctcc cgggcccaaa 3960
ggcgagaagg gggaacaggg cgaggatggc aagactgagg gggcccccgg gccaccagga 4020
gagcggggtc ctgtgggtga tcgaggagac cgtggggagc caggcgaccc tggataccct 4080
ggtcaagagg gtgttcaagg cctccgtgga gaaccaggcc agcagggcca gcccgggcat 4140
ccaggacccc ggggacgccc aggacccaaa ggatcaaaag gcgaagaggg cccaaaggga 4200
aagccaggca aggcgggggc atcaggccgg agggggaccc aggggcttca agggctgcca 4260
gggccgagag gtgtagtagg gagacagggc cctgagggca tggctggaca agatgggaat 4320
cctggcaggg acggtcggcc aggatatcag ggagagcagg gaaatgatgg ggaccctggc 4380
cccgtgggcc ctgctgggag aagagggaat ccaggtgtgg ctggcttgcc tggagcacag 4440
gggcctccag gattcaaggg tgaaagtggg ttacctgggc aactgggtcc ccctggaaaa 4500
cgagggacag aaggtggaac ggggcttcct gggaaccagg gggagccagg atccaaaggc 4560
cagccgggtg actctggcga gatgggcttc ccaggagtgg ctggcctctt tggacccaag 4620
ggtccccctg gagacattgg cttcaaaggc atccaaggcc ctcggggtcc tcctggcttg 4680
atgggaaagg aaggtatcat tgggcccccc ggaatgctgg gaccttctgg actcccgggt 4740
cccaaaggtg acagaggcag ccgaggggac tggggactgc aaggcccaag gggtcctcct 4800
ggtccgaggg ggcggccagg tccaccgggc cctccttggc atcctgtcca gtttcaacaa 4860
gatgaccttg aggcagcttt ccaaacgtgg atggatgctc acggagcagt cagattggag 4920
caggggtaca gctatccgga ccagctgatg ctagaccagg gaggggagat cttcaaaacc 4980
ttacactacc tcagcaacct catccagagc attaagacgc ccttgggcac caaggagaac 5040
ccagcccggg tctgccggga cctcatggac tgcgaacaga agatggcgga tggtatctac 5100
tgggtggacc ccaacctcgg ctgctcctct gataccatcg aagtctcctg caactttaca 5160
catggtgggc agacttgcct gaagcctatc acggcctcca aggcagagtt tgctgttagt 5220
cgggtccaga tgaatttctt gcacctgctc agctctgagg ggacacagca catcacaatc 5280
cactgcctga acatgacggt gtggcaggag ggacctgcac gcccctctgc caggcaagct 5340
gtgcgcttcc gtgcctggaa cggacaggtc tttgaagctg ggggtcaatt caggccagag 5400
gtgtctatgg atggctgcaa ggtccatgat ggccgctggc atcagacact attcaccttc 5460
cggacccagg acccccagca gctgcccatt gtcagtgtgg acaaccttcc acctgtctcg 5520
tcagggaagc agtaccgcct ggaagttgga cctgcatgct tcctctga 5568
<210> 6
<211> 1855
<212> PRT
<213> 褐家鼠(Rattus norvegicus)
<400> 6
Met Gly Leu Ala Arg Ala Thr Ala Gly Leu Gly Pro Cys Cys Pro Pro
1 5 10 15
Ala Pro Ala Leu Leu Gly Ala Gly Leu Arg Trp Gly Gly Phe Leu Phe
20 25 30
Ala Trp Ile Leu Val Ser Phe Ser Cys His Leu Ala Ser Thr Gln Gly
35 40 45
Ala Pro Glu Asp Val Asp Val Leu Gln Arg Leu Gly Leu Ser Trp Thr
50 55 60
Lys Ala Gly Gly Gly Arg Ser Pro Ala Pro Pro Gly Val Ile Pro Phe
65 70 75 80
Pro Ser Gly Phe Ile Phe Thr Gln Arg Ala Lys Leu Gln Ala Pro Thr
85 90 95
Thr Asn Val Leu Pro Thr Thr Leu Gly Arg Glu Leu Ala Leu Val Leu
100 105 110
Ser Leu Cys Ser His Arg Val Asn His Ala Phe Leu Phe Ala Ile Arg
115 120 125
Ser Arg Lys His Arg Leu Gln Leu Gly Leu Gln Phe Leu Pro Gly Arg
130 135 140
Thr Leu Val His Leu Gly Pro Arg Gln Ser Val Ala Phe Asp Leu Asp
145 150 155 160
Val His Asp Gly Arg Trp His His Leu Ala Leu Glu Leu Arg Gly Arg
165 170 175
Thr Val Thr Leu Val Thr Ala Cys Gly Gln His Arg Val Pro Val Pro
180 185 190
Leu Pro Ser Arg Arg Asp Ser Met Leu Asp Pro Gln Gly Ser Phe Leu
195 200 205
Leu Gly Lys Met Asn Pro Arg Ala Val Gln Phe Glu Gly Ala Leu Cys
210 215 220
Gln Phe Ser Ile His Pro Val Ala Gln Val Ala His Asn Tyr Cys Ala
225 230 235 240
His Leu Arg Glu Arg Cys Arg Gln Val Asp Thr Tyr Gly Pro Gln Val
245 250 255
Gly Ala Leu Phe Pro Trp Asp Ser Gly Pro Ala Phe Ala Leu His Pro
260 265 270
Glu Pro Ala Leu Leu Gly Leu Gly Asn Leu Thr Arg Asn Pro Ala Thr
275 280 285
Leu Gly Ser Arg Pro Ile Ser Arg Gly Leu Met Val Thr Met Ala Pro
290 295 300
Ala Val Pro Thr Lys Pro Leu Arg Met Val His Gln Asp Val Ser Lys
305 310 315 320
Leu Gly Ser Ser Gln Thr Pro Leu Val Pro Ala Lys Gln Ser Ala Arg
325 330 335
Lys Thr Pro Ser Pro Phe Pro Ser Ala Ala Leu Ala Asn Ser Thr Arg
340 345 350
Val Phe His Ser Ala Pro Ala Gln Pro Arg Gln Ile Thr Ala Thr Ser
355 360 365
Pro Thr Lys Arg Pro Pro Thr Lys Pro Ser Val Ser Ser Leu Ser Val
370 375 380
Thr Pro Met Lys Ser Pro Gln Ala Ile Gln Lys Ala Gly Thr Pro Ser
385 390 395 400
Phe Ser Arg Pro Ile Pro Thr Thr Gln Lys Pro Thr Pro Leu Thr Ser
405 410 415
His Pro Ser Pro Ser Lys Val Ser Ser Ala Thr Val Arg Pro Val Gln
420 425 430
Lys Thr Phe Met Thr Pro Gln Pro Pro Thr Leu Ser Pro Gln Ala Leu
435 440 445
His Pro Ile Thr Gly Leu Pro Lys Lys Phe Thr Ile Pro Thr Val Ala
450 455 460
Lys Pro Gln Ser Lys Met Thr Ser Trp Ala Ser Lys Pro Val Leu Ala
465 470 475 480
Arg Thr Asn Val Pro Lys Ala Leu Glu Gln Thr Val Val Ala Gln Ser
485 490 495
Ser Val Ser Tyr Leu Gly Ser Gln Thr Leu Ala Thr Ala Leu Pro Pro
500 505 510
Leu Gly Val Gly Asn Ser Arg Met Met Pro Ser Thr Arg Asp Ser Thr
515 520 525
Ser Thr Pro Ala Gly Ser Lys Lys Ile Thr Gly Leu Glu Ala Ser Lys
530 535 540
Lys Thr Arg His Lys Ser Ser Pro Arg Lys Pro Ile Pro Leu Ser Ser
545 550 555 560
Gly Lys Thr Ala Arg Asp Ala Ser Pro Arg Asp Leu Thr Thr Lys Pro
565 570 575
Ser Gln Leu Ser Thr Pro Ala Leu Val Leu Ala Pro Ala His Leu Leu
580 585 590
Ser Ser Ser Pro Gln Pro Thr Ser Ser Ser Phe Ser Phe Phe His Leu
595 600 605
Pro Glu Pro Thr Pro Phe Leu Met Leu Met Gly Pro Pro Gly Ser Lys
610 615 620
Gly Asp Cys Gly Leu Pro Gly Pro Pro Gly Leu Pro Gly Leu Pro Gly
625 630 635 640
Ser Pro Gly Pro Arg Gly Pro Arg Gly Pro Pro Gly Pro Phe Gly Asn
645 650 655
Pro Gly Leu Pro Gly Pro Pro Gly Ala Lys Gly Gln Lys Gly Asp Pro
660 665 670
Gly Leu Ser Pro Gly Gln Ala His Asp Gly Ala Lys Gly Asn Met Gly
675 680 685
Leu Pro Gly Leu Ala Gly Asn Pro Gly Pro Met Gly Arg Lys Gly His
690 695 700
Lys Gly His Pro Gly Ala Ala Gly His Pro Gly Glu Gln Gly Gln Pro
705 710 715 720
Gly Pro Glu Gly Ser Pro Gly Ala Lys Gly Tyr Pro Gly Arg Gln Gly
725 730 735
Phe Pro Gly Pro Val Gly Asp Pro Gly Pro Lys Gly Ser Arg Gly Tyr
740 745 750
Ile Gly Leu Pro Gly Leu Phe Gly Leu Pro Gly Ser Asp Gly Glu Arg
755 760 765
Gly Leu Pro Gly Ile Pro Gly Lys Arg Gly Glu Met Gly Arg Pro Gly
770 775 780
Phe Pro Gly Asp Phe Gly Glu Arg Gly Pro Pro Gly Leu Asp Gly Asn
785 790 795 800
Pro Gly Glu Ile Gly Leu Pro Gly Pro Pro Gly Val Leu Gly Leu Leu
805 810 815
Gly Asp Met Gly Ala Leu Gly Pro Val Gly Tyr Pro Gly Pro Lys Gly
820 825 830
Met Lys Gly Leu Met Gly Gly Val Gly Glu Pro Gly Leu Lys Gly Asp
835 840 845
Lys Gly Glu Gln Gly Val Pro Gly Val Ser Gly Asp Pro Gly Phe Gln
850 855 860
Gly Asp Lys Gly Ser His Gly Leu Pro Gly Phe Pro Gly Ala Arg Gly
865 870 875 880
Lys Pro Gly Pro Met Gly Lys Ala Gly Asp Lys Gly Ser Leu Gly Leu
885 890 895
Pro Gly Pro Pro Gly Pro Glu Gly Phe Pro Gly Asp Ile Gly Pro Pro
900 905 910
Gly Asp Asn Gly Pro Glu Gly Met Lys Gly Lys Pro Gly Ala Arg Gly
915 920 925
Leu Pro Gly Pro Pro Gly Gln Leu Gly Pro Glu Gly Asp Glu Gly Pro
930 935 940
Met Gly Pro Pro Gly Val Pro Gly Leu Glu Gly Gln Pro Gly Arg Lys
945 950 955 960
Gly Phe Pro Gly Arg Pro Gly Leu Asp Gly Ser Lys Gly Glu Pro Gly
965 970 975
Asp Pro Gly Arg Pro Gly Pro Val Gly Glu Gln Gly Leu Met Gly Phe
980 985 990
Val Gly Leu Val Gly Glu Pro Gly Ile Val Gly Glu Lys Gly Asp Arg
995 1000 1005
Gly Val Met Gly Pro Pro Gly Ala Pro Gly Pro Lys Gly Ser Met
1010 1015 1020
Gly His Pro Gly Thr Pro Gly Gly Val Gly Asp Pro Gly Glu Pro
1025 1030 1035
Gly Pro Trp Gly Pro Pro Gly Ser Arg Gly Leu Pro Gly Met Arg
1040 1045 1050
Gly Ala Lys Gly His Arg Gly Pro Arg Gly Pro Asp Gly Pro Ala
1055 1060 1065
Gly Glu Gln Gly Ser Lys Gly Leu Lys Gly Arg Val Gly Pro Arg
1070 1075 1080
Gly Arg Pro Gly Gln Pro Gly Gln Gln Gly Ala Ala Gly Glu Arg
1085 1090 1095
Gly His Ser Gly Ala Lys Gly Phe Leu Gly Ile Pro Gly Pro Ser
1100 1105 1110
Gly Pro Pro Gly Ala Lys Gly Leu Pro Gly Glu Pro Gly Ser Gln
1115 1120 1125
Gly Pro Gln Gly Pro Val Gly Pro Pro Gly Glu Met Gly Pro Lys
1130 1135 1140
Gly Pro Pro Gly Ala Val Gly Glu Pro Gly Leu Pro Gly Asp Ser
1145 1150 1155
Gly Met Lys Gly Asp Leu Gly Pro Leu Gly Pro Pro Gly Glu Gln
1160 1165 1170
Gly Leu Ile Gly Gln Arg Gly Glu Pro Gly Leu Glu Gly Asp Leu
1175 1180 1185
Gly Pro Val Gly Pro Asp Gly Leu Lys Gly Asp Arg Gly Asp Pro
1190 1195 1200
Gly Pro Asp Gly Glu His Gly Glu Lys Gly Gln Glu Gly Leu Lys
1205 1210 1215
Gly Glu Glu Gly Leu Pro Gly Pro Pro Gly Ile Thr Gly Val Arg
1220 1225 1230
Gly Arg Glu Gly Lys Pro Gly Ser Gln Gly Glu Lys Gly Gln Arg
1235 1240 1245
Gly Ala Lys Gly Ala Lys Gly Tyr Gln Gly Gln Leu Gly Glu Met
1250 1255 1260
Gly Ile Pro Gly Asp Pro Gly Pro Pro Gly Thr Pro Gly Pro Lys
1265 1270 1275
Gly Ser Arg Gly Thr Leu Gly Pro Met Gly Ala Pro Gly Arg Met
1280 1285 1290
Gly Ala Gln Gly Glu Pro Gly Leu Ala Gly Tyr Asn Gly His Lys
1295 1300 1305
Gly Ile Thr Gly Pro Leu Gly Pro Pro Gly Pro Lys Gly Glu Lys
1310 1315 1320
Gly Glu Gln Gly Glu Asp Gly Lys Thr Glu Gly Ala Pro Gly Pro
1325 1330 1335
Pro Gly Glu Arg Gly Pro Val Gly Asp Arg Gly Asp Arg Gly Glu
1340 1345 1350
Pro Gly Asp Pro Gly Tyr Pro Gly Gln Glu Gly Val Gln Gly Leu
1355 1360 1365
Arg Gly Glu Pro Gly Gln Gln Gly Gln Pro Gly His Pro Gly Pro
1370 1375 1380
Arg Gly Arg Pro Gly Pro Lys Gly Ser Lys Gly Glu Glu Gly Pro
1385 1390 1395
Lys Gly Lys Pro Gly Lys Ala Gly Ala Ser Gly Arg Arg Gly Thr
1400 1405 1410
Gln Gly Leu Gln Gly Leu Pro Gly Pro Arg Gly Val Val Gly Arg
1415 1420 1425
Gln Gly Pro Glu Gly Met Ala Gly Gln Asp Gly Asn Pro Gly Arg
1430 1435 1440
Asp Gly Arg Pro Gly Tyr Gln Gly Glu Gln Gly Asn Asp Gly Asp
1445 1450 1455
Pro Gly Pro Val Gly Pro Ala Gly Arg Arg Gly Asn Pro Gly Val
1460 1465 1470
Ala Gly Leu Pro Gly Ala Gln Gly Pro Pro Gly Phe Lys Gly Glu
1475 1480 1485
Ser Gly Leu Pro Gly Gln Leu Gly Pro Pro Gly Lys Arg Gly Thr
1490 1495 1500
Glu Gly Gly Thr Gly Leu Pro Gly Asn Gln Gly Glu Pro Gly Ser
1505 1510 1515
Lys Gly Gln Pro Gly Asp Ser Gly Glu Met Gly Phe Pro Gly Val
1520 1525 1530
Ala Gly Leu Phe Gly Pro Lys Gly Pro Pro Gly Asp Ile Gly Phe
1535 1540 1545
Lys Gly Ile Gln Gly Pro Arg Gly Pro Pro Gly Leu Met Gly Lys
1550 1555 1560
Glu Gly Ile Ile Gly Pro Pro Gly Met Leu Gly Pro Ser Gly Leu
1565 1570 1575
Pro Gly Pro Lys Gly Asp Arg Gly Ser Arg Gly Asp Trp Gly Leu
1580 1585 1590
Gln Gly Pro Arg Gly Pro Pro Gly Pro Arg Gly Arg Pro Gly Pro
1595 1600 1605
Pro Gly Pro Pro Trp His Pro Val Gln Phe Gln Gln Asp Asp Leu
1610 1615 1620
Glu Ala Ala Phe Gln Thr Trp Met Asp Ala His Gly Ala Val Arg
1625 1630 1635
Leu Glu Gln Gly Tyr Ser Tyr Pro Asp Gln Leu Met Leu Asp Gln
1640 1645 1650
Gly Gly Glu Ile Phe Lys Thr Leu His Tyr Leu Ser Asn Leu Ile
1655 1660 1665
Gln Ser Ile Lys Thr Pro Leu Gly Thr Lys Glu Asn Pro Ala Arg
1670 1675 1680
Val Cys Arg Asp Leu Met Asp Cys Glu Gln Lys Met Ala Asp Gly
1685 1690 1695
Ile Tyr Trp Val Asp Pro Asn Leu Gly Cys Ser Ser Asp Thr Ile
1700 1705 1710
Glu Val Ser Cys Asn Phe Thr His Gly Gly Gln Thr Cys Leu Lys
1715 1720 1725
Pro Ile Thr Ala Ser Lys Ala Glu Phe Ala Val Ser Arg Val Gln
1730 1735 1740
Met Asn Phe Leu His Leu Leu Ser Ser Glu Gly Thr Gln His Ile
1745 1750 1755
Thr Ile His Cys Leu Asn Met Thr Val Trp Gln Glu Gly Pro Ala
1760 1765 1770
Arg Pro Ser Ala Arg Gln Ala Val Arg Phe Arg Ala Trp Asn Gly
1775 1780 1785
Gln Val Phe Glu Ala Gly Gly Gln Phe Arg Pro Glu Val Ser Met
1790 1795 1800
Asp Gly Cys Lys Val His Asp Gly Arg Trp His Gln Thr Leu Phe
1805 1810 1815
Thr Phe Arg Thr Gln Asp Pro Gln Gln Leu Pro Ile Val Ser Val
1820 1825 1830
Asp Asn Leu Pro Pro Val Ser Ser Gly Lys Gln Tyr Arg Leu Glu
1835 1840 1845
Val Gly Pro Ala Cys Phe Leu
1850 1855
Claims (22)
1.一种经遗传修饰的啮齿动物,其基因组包含内源性啮齿动物Col27a1基因中的突变,其中所述突变等同于导致在人COL27A1蛋白的氨基酸位置697处的Gly至Arg取代(G697R)的在人COL27A1基因中的突变。
2.如权利要求1所述的啮齿动物,其中所述啮齿动物是小鼠或大鼠。
3.如权利要求1所述的啮齿动物,其中所述啮齿动物是小鼠,并且所述内源性小鼠Col27a1基因中的所述突变导致在小鼠Col27a1蛋白中与所述人COL27A1蛋白的氨基酸位置697相对应的氨基酸位置处的Gly至Arg取代。
4.如权利要求3所述的啮齿动物,其中所述小鼠Col27a1蛋白中的氨基酸位置是位置682。
5.如权利要求1所述的啮齿动物,其中所述啮齿动物是大鼠,并且所述内源性大鼠Col27a1基因中的所述突变导致在大鼠Col27a1蛋白中与所述人COL27A1蛋白的氨基酸位置697相对应的氨基酸位置处的Gly至Arg取代。
6.如权利要求5所述的啮齿动物,其中所述大鼠Col27a1蛋白中的氨基酸位置是位置691。
7.如权利要求1所述的啮齿动物,其中所述啮齿动物对于所述内源性啮齿动物Col27a1基因中的突变是纯合的。
8.如权利要求7所述的啮齿动物,其中所述啮齿动物表现出与斯蒂尔综合征相关的一种或多种异常。
9.如权利要求8所述的啮齿动物,其中所述异常选自由以下项组成的组:如与野生型啮齿动物相比,在脊柱中严重的胸椎后凸、体长减小、长骨长度降低、骨矿物质含量(BMC)降低、头骨形状异常和体重减轻。
10.一种分离的啮齿动物细胞或组织,其基因组包含内源性啮齿动物Col27a1基因中的突变,其中所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变。
11.如权利要求10所述的分离的细胞或组织,其中所述啮齿动物是小鼠或大鼠。
12.一种分离的啮齿动物胚胎干(ES)细胞,其基因组包含内源性啮齿动物Col27a1基因中的突变,其中所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变。
13.如权利要求12所述的分离的ES细胞,其中所述ES细胞是小鼠ES细胞或大鼠ES细胞。
14.一种制备Col27a1突变型啮齿动物的方法,所述方法包括:
修饰啮齿动物基因组,使得经修饰的基因组包含在所述内源性啮齿动物Col27a1基因中的突变,所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变;以及
制备包含经修饰的基因组的Col27a1突变型啮齿动物。
15.如权利要求14所述的方法,其中所述啮齿动物基因组通过以下包括以下步骤的过程来修饰:
(a)将靶向核酸引入啮齿动物ES细胞的基因组中,以获得突变型啮齿动物ES细胞,其基因组包含在所述内源性啮齿动物Col27a1基因中的突变;以及
(b)使用(a)的所述突变型啮齿动物ES细胞制备Col27a1突变型啮齿动物。
16.如权利要求14所述的方法,其中所述啮齿动物是小鼠或大鼠。
17.一种靶向核酸构建体,其包含
将要在内源性啮齿动物Col27a1基因座处整合到啮齿动物Col27A1基因中的核酸序列,其侧翼为与所述啮齿动物Col27A1基因座处的核苷酸序列同源的5’核苷酸序列和3’核苷酸序列,其中所述核酸序列整合到所述啮齿动物Col27a1基因中导致在所述内源性啮齿动物Col27a1基因中的突变,所述突变等同于导致在人COL27A1蛋白中的G697R取代的在人COL27A1基因中的突变。
18.如权利要求17所述的靶向核酸,其中所述啮齿动物是小鼠或大鼠。
19.一种鉴定用于治疗斯蒂尔综合征的治疗剂的方法,所述方法包括
(a)向如权利要求1所述的啮齿动物施用药剂;
(b)进行一种或多种测定以确定所述药剂是否对与斯蒂尔综合征相关的一种或多种异常具有效果;以及
(c)当所述药剂对与斯蒂尔综合征相关的一种或多种异常有治疗效果时,将所述药剂鉴定为治疗剂。
20.如权利要求19所述的方法,其中在出生时或出生后不久将所述药剂施用至所述啮齿动物。
21.如权利要求19所述的方法,其中所述啮齿动物是大鼠或小鼠。
22.如权利要求1所述的啮齿动物作为斯蒂尔综合征的啮齿动物模型的用途。
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US16/002,233 US10463029B1 (en) | 2018-06-07 | 2018-06-07 | Rodent model of steel syndrome |
US16/002,233 | 2018-06-07 | ||
PCT/US2019/035693 WO2019236783A1 (en) | 2018-06-07 | 2019-06-06 | A rodent model of steel syndrome |
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US (1) | US10463029B1 (zh) |
EP (1) | EP3802586A1 (zh) |
JP (1) | JP2021526019A (zh) |
KR (1) | KR20210022039A (zh) |
CN (1) | CN112351995A (zh) |
AU (1) | AU2019282699A1 (zh) |
CA (1) | CA3098037A1 (zh) |
MX (1) | MX2020013283A (zh) |
WO (1) | WO2019236783A1 (zh) |
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CN107105633A (zh) * | 2014-11-24 | 2017-08-29 | 瑞泽恩制药公司 | 表达人源化cd3复合物的非人类动物 |
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AU2005295269B2 (en) | 2004-10-19 | 2010-05-13 | Regeneron Pharmaceuticals, Inc. | Method for generating an animal homozygous for a genetic modification |
WO2011020005A1 (en) | 2009-08-14 | 2011-02-17 | Regeneron Pharmaceuticals, Inc. | miRNA-REGULATED DIFFERENTIATION-DEPENDENT SELF-DELETING CASSETTE |
WO2014130706A1 (en) | 2013-02-20 | 2014-08-28 | Regeneron Pharmaceuticals, Inc. | Genetic modification of rats |
HUE056903T2 (hu) | 2013-04-16 | 2022-04-28 | Regeneron Pharma | Patkány genom célzott módosítása |
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- 2018-06-07 US US16/002,233 patent/US10463029B1/en active Active
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- 2019-06-06 MX MX2020013283A patent/MX2020013283A/es unknown
- 2019-06-06 AU AU2019282699A patent/AU2019282699A1/en not_active Abandoned
- 2019-06-06 EP EP19739426.5A patent/EP3802586A1/en not_active Withdrawn
- 2019-06-06 WO PCT/US2019/035693 patent/WO2019236783A1/en unknown
- 2019-06-06 CA CA3098037A patent/CA3098037A1/en active Pending
- 2019-06-06 KR KR1020217000492A patent/KR20210022039A/ko not_active Application Discontinuation
- 2019-06-06 CN CN201980035497.1A patent/CN112351995A/zh active Pending
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CN1292638A (zh) * | 1998-01-08 | 2001-04-25 | 第一制药株式会社 | 基因突变动物 |
AU2012216725A1 (en) * | 2005-07-11 | 2012-10-04 | Globeimmune, Inc | Compositions and methods for eliciting an immune response to escape mutants of targeted therapies |
CN101588801A (zh) * | 2006-11-28 | 2009-11-25 | 诺瓦提斯公司 | Iap抑制剂和flt3抑制剂的组合 |
JP2010207097A (ja) * | 2009-03-06 | 2010-09-24 | Chube Univ | 難聴モデル動物及びその用途 |
CN107105633A (zh) * | 2014-11-24 | 2017-08-29 | 瑞泽恩制药公司 | 表达人源化cd3复合物的非人类动物 |
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KR20210022039A (ko) | 2021-03-02 |
WO2019236783A1 (en) | 2019-12-12 |
US10463029B1 (en) | 2019-11-05 |
JP2021526019A (ja) | 2021-09-30 |
AU2019282699A1 (en) | 2020-12-24 |
EP3802586A1 (en) | 2021-04-14 |
CA3098037A1 (en) | 2019-12-12 |
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