CN108659113B - 一种辅助癫痫诊断的标志物及其检测试剂盒 - Google Patents

Abstract

本发明公开了一种辅助癫痫诊断的标志物及其检测试剂盒，涉及癫痫诊断领域。本发明的研究通过对一个癫痫家系患者的成员的GPR98基因的检测发现，该家系中患有癫痫的成员的GPR98基因上具有突变c.A6812G，该基因突变导致其对应的GPR98蛋白的第2271位氨基酸由谷氨酰胺(Q)变异为精氨酸(R)，为错义突变。含有c.A6812G突变的核酸分子，或者含有突变p.Q2271R的蛋白均可以作为癫痫诊断的生物标志物，从分子水平上为癫痫的诊断提供一种快速、可靠的检测辅助标记物。

Description

一种辅助癫痫诊断的标志物及其检测试剂盒

技术领域

本发明涉及癫痫诊断领域，具体而言，涉及一种辅助癫痫诊断的标志物及其检测试剂盒。

背景技术

癫痫是慢性反复发作性短暂脑功能失调综合征。以脑部神经元高度同步化异常放电引起反复痫性发作为特征。癫痫是神经系统常见疾病之一，患病率仅次于脑卒中。癫痫的发病率与年龄有关。一般认为1岁以内患病率最高，1～10岁以后逐渐降低。我国癫痫患者男女之比为(1.15-1.7):1。

癫痫病因极其复杂，可分三大类，并存在多种影响发病的因素：

1.特发性癫痫

可疑遗传倾向且无其他明显病因，常在特定年龄段起病，有特征性临床及脑电图表现，诊断较明确。

2.症状性癫痫

中枢神经系统病变影响结构或功能等，如染色体异常、局灶性或弥漫性脑部疾病，以及某些系统性疾病所致。

(1)局限性或弥漫性脑部疾病①先天性异常胚胎发育中各种病因导致脑穿通畸形、小头畸形、先天性脑积水胼胝体缺如及大脑皮质发育不全，围生期胎儿脑损伤等；②获得性脑损伤如脑外伤，颅脑手术后，脑卒中后，颅内感染后，急性酒精中毒；③产伤所致新生儿癫痫发生率约为1％，分娩时合并产伤多伴脑出血或脑缺氧损害，新生儿合并脑先天发育畸形或产伤，癫痫发病率高达25％；④感染包括中枢神经系统细菌、病毒、真菌、寄生虫、螺旋体感染及AIDS神经系统并发症等；⑤脑血管疾病如脑动静脉畸形、脑梗死和脑出血等；⑥颅内原发性肿瘤如神经胶质瘤、脑膜瘤等；⑦遗传代谢性疾病如结节性硬化、脑-面血管瘤病、苯丙酮酸尿症等；⑧神经系统变性疾病如Alzheimer病、Pick病等约1/3的患者合并癫痫发作。

(2)系统性疾病①缺氧性脑病如心搏骤停、CO中毒窒息、麻醉意外和呼吸衰竭等可引起肌阵挛性发作或全身性大发作；②代谢性脑病如低血糖症，其他代谢及内分泌障碍如高血糖症、低钙血症、低钠血症，以及尿毒症、肝性脑病和甲状腺毒血症等均可导致癫痫发作；③心血管疾病如心脏骤停、高血压脑病等；④热性惊厥热性发作；⑤子痫；⑥中毒如酒精、异烟肼、卡巴唑等药物及铅、铊等重金属中毒。

3.隐源性癫痫

较多见，临床表现提示症状性癫痫，但未找到明确病因，可在特殊年龄段起病，无特定临床和脑电图表现。

癫痫的临床表现有以下：

1.全面强直-阵挛发作(大发作)

系指全身肌肉抽动及意识丧失的发作。以产伤、脑外伤、脑瘤等较常见。强直-阵挛发作可发生在任何年龄，是各种癫痫中最常见的发作类型。其典型发作可分为强直期、阵挛期、恢复期三个临床阶段。发作期间脑电图为典型的爆发性多棘波和棘-慢波综合，每次棘-慢波综合可伴有肌肉跳动。

2.单纯部分发作

是指脑的局部皮质异常放电而引起的与该部位的功能相对应的症状，发作时意识始终存在，包括运动、感觉、自主神经、精神症状及体征。分为四组：①伴运动症状者；②伴躯体感觉或特殊感觉症状者；③伴自主神经症状和体征者；④伴精神症状者。

3.复杂部分发作

习惯上又称精神运动性发作，伴有意识障碍。先兆多在意识丧失前或即将丧失时发生，发作后不能或部分不能回忆发作细节。4.失神发作(小发作)

其典型表现为意识障碍，而不伴先兆或发作后症状。

5.癫痫持续状态

是指单次癫痫发作超过5分钟，或者短期内癫痫频繁发作，以致患者尚未从前一次发作中完全恢复而又有另一次发作。癫痫持续状态是一种需要抢救的急症。

癫痫的治疗可分为控制发作、病因治疗、外科治疗、一般卫生及预防五个方面。其中最重要的是控制发作，目前以药物治疗为主。

临床上根据癫痫发作类型选用抗癫痫药物，一旦找到可以完全控制发作的药物和剂量，就应不间断地应用。一般应于发作完全控制后，如无不良反应再继续服用3～5年，方可考虑逐渐停药。目前多主张用单药治疗，确认单药治疗失败后，方可加用第2种药物。如失神发作或肌阵挛发作无法用单药控制者，可合用乙琥胺和丙戊酸钠，或其一加用苯二氮类。对合并多种发作类型者可以根据发作类型合理联合用药，但以不超过3种药物为宜。

用药宜从小剂量开始，然后逐渐增量，以既能控制发作，又不产生毒性反应的最小有效剂量为宜。换药宜采取先加用新药及后递减旧药的原则。不能骤然停药。

有些器质性脑病的癫痫患者可能需要终身服药；有人主张发病年龄大于30岁者需谨慎停药，因其停药后复发率较高，需长期服药或终身服药。但仍有10％～15％患者难以控制发作，可以采用外科治疗。

在预防方面：

1.预防癫痫病的发生，应详细地进行家系调查，了解患者双亲同胞和近亲中是否有癫痫发作及其发作特点，对能引起智力低下和癫痫的一些严重遗传性疾病，应进行产前诊断或新生儿期过筛检查，以决定终止妊娠或早期进行治疗。防止分娩意外，新生儿产伤是癫痫发病的重要原因之一，避免产伤对预防癫痫有重要意义。

2.对癫痫患者要及时诊断，及早治疗，治疗越早脑损伤越小，复发越少，预后越好。去除或减轻引起癫痫的原发病如颅内占位性疾病、代谢异常、感染等，对反复发作的病例也有重要意义。

3.癫痫是一种慢性疾病，可迁延数年、甚至数十年之久，因而可对患者身体、精神、婚姻以及社会经济地位等，造成严重的不良影响。患者在家庭关系、学校教育和就业等方面的不幸和挫折、文体活动方面的限制等，可使患者产生耻辱感和悲观心理，从而严重影响患者的身心发育，这就要求社会各界对癫痫患者给予理解和支持。

早诊断早治疗是防治癫痫的有效方法，但目前缺乏癫痫诊断相关的标志物。

鉴于此，特提出本发明。

发明内容

本发明的目的在于提供一种用于辅助癫痫诊断的生物标志物，该生物标志物可以用于辅助癫痫的诊断，为癫痫的诊断提供一种新的思路。

本发明的另一目的在于提供上述生物标志物的应用。

本发明的另一目的在于提供一种辅助癫痫诊断的试剂盒。

本发明的另一目的在于提供一种用于辅助癫痫诊断的基因芯片。

本发明是这样实现的：

第一方面，本发明提供了一种辅助癫痫诊断的生物标志物，其为核酸分子，其相对于正常GPR98基因的编码序列具有突变c.A6812G。

GPR98基因编码的蛋白属于G蛋白偶联受体超家族成员，该蛋白包含一个有7个跨膜蛋白受体的结构域，结合钙离子，在中枢神经系统里面表达。该基因突变与Usher综合征2型和家族性热性惊厥有关。已报到一些选择性剪切转录本。

进一步地，在本发明的一些实施方案中，所述标志物的碱基序列如SEQ ID NO.1所示。

本发明的研究通过对一个癫痫家系患者的成员的GPR98基因的检测测序发现，该家系中患有癫痫的成员的GPR98基因上具有突变c.A6812G，该基因突变导致其对应的GPR98蛋白的第2271位氨基酸由谷氨酰胺(Q)变异为精氨酸(R)，为错义突变。该变异不属于多态性位点，在人群中发生频率极低。在HGMD专业版数据库中未见报道。经家系验证分析，受检人(图1中4号成员)之父(图1中3号成员)该位点无变异，受检人之母(图1中2号成员)该位点杂合变异，受检人之姥爷(图1中1号成员)该位点杂合变异。

因此，含有c.A6812G突变的核酸分子即相对于正常GPR98基因的编码序列具有突变c.A6812G的核酸片段，或者含有突变p.Q2271R的蛋白均可以作为癫痫诊断的生物标志物，从分子水平上为癫痫的诊断提供一种快速、可靠的检测辅助标记物。

第二方面，本发明提供了一种辅助癫痫诊断的生物标志物，其为蛋白或多肽，其相对于正常GPR98蛋白具有突变p.Q2271R。

进一步地，在本发明的一些实施方案中，所述标志物的氨基酸序列如SEQ ID NO.2所示。

另一方面，本发明提供了检测第一方面所述的标志物的引物或探针、或检测权第二方面所述的生物标志物的抗体在制备癫痫辅助诊断试剂盒、癫痫产前诊断试剂盒或新生儿癫痫筛查试剂盒中的应用。

基于本发明的研究成果，本领域技术人员应当很容易将用于检测含有c.A6812G突变的GPR98突变基因的引物或探针，以及用于检测含有p.Q2271R突变的GPR98突变蛋白的抗体用于制备癫痫辅助诊断试剂盒、癫痫产前诊断试剂盒以及新生儿癫痫筛查试剂盒等领域中。

或者将检测含有c.A6812G突变的GPR98突变基因的探针用于制备辅助癫痫诊断的基因芯片中。

进一步，在本发明的一些实施方案中，所述探针相对于正常GPR98基因的编码序列的第6812位的碱基为G。

另一方面，本发明提供了一种辅助癫痫诊断的试剂盒，其含有用于检测第一方面所述的生物标志物的引物或探针；

或者所述试剂盒含有检测第二方面所述的生物标志物的抗体。

另一方面，本发明提供了一种用于辅助癫痫诊断的基因芯片，该基因芯片上含有用于与目标片段特异性结合的探针，所述目标片段性相对于正常GPR98基因的编码序列具有突变c.A6812G。

所述探针与目标片段特异性结合的区域涵盖如下位置：相对于正常GPR98基因的第6812位。

进一步，在本发明的一些实施方案中，所述探针相对于正常GPR98基因编码序列的第6812位的碱基为G。

进一步，在本发明的一些实施方案中，所述目标片段为来自待测主体的GPR98基因的编码序列。

进一步，在本发明的一些实施方案中，所述主体为人。

附图说明

为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。

图1为本发明实施例1中的受检对象癫痫患者家系的遗传家系图谱；

图2-A为本发明实施例1中的遗传家系图谱中的4号成员的GPR98基因测序结果图；

图2-B为本发明实施例1中的遗传家系图谱中的1号成员的GPR98基因测序结果图；

图2-C为本发明实施例1中的遗传家系图谱中的2号成员的GPR98基因测序结果图；

图2-D为本发明实施例1中的遗传家系图谱中的3号成员的GPR98基因测序结果图。

具体实施方式

为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。

以下结合实施例对本发明的特征和性能作进一步的详细描述。

实施例1

1癫痫患者家系的GPR98基因突变检测

1.1对象：来自重庆市沙坪坝区杨氏癫痫家系先证者及其家系成员，该家系的遗传图谱如图1所示，包括3例癫痫患者(图中1 2 4号成员)，1例正常家庭成员(图中3号成员)；1号、2号、4号：全面强直-阵挛发作；3号：未患病。对所有1-4号家庭成员进行详细体格检查，在签署知情同意书后每人采集血液样本。

1.2测序：

将采集的血液样本送北京迈基诺基因科技股份有限公司测序进行癫痫基因突变筛查及验证，分析临床表型、基因型的关系，结果如下：

将测得的序列与正常GPR98基因标准序列比对(https://www.ncbi.nlm.nih.gov/nuccore/NM_032119.3)，测序结果如图2-A所示，先证者即4号成员GPR98基因有1个杂合突变：c.6812A>G(编码区第6812号核苷酸由腺嘌呤变异为鸟嘌呤)，导致氨基酸改变p.Q2271R(第2271号氨基酸由谷氨酰胺变异为精氨酸)，为错义突变。该变异不属于多态性位点，在人群中发生频率极低。在HGMD专业版数据库中未见报道。经家系验证分析，先证者(4号成员)之父(图1中3号成员)该位点无变异，3号成员的测序结果如图2-D所示，先证者之母(图1中2号成员)该位点杂合变异，2号成员的测序结果如图2-C所示，先证者之姥爷(图1中1号成员)该位点杂合变异，1号成员的测序结果如图2-B所示。图2的A-D中，箭头所示为GPR98基因6812位点的测序结果，1、2、4号成员在该位点的测序结果为均杂合突变(基因型为AG型)，3号成员在该位点的测序结果为无突变(基因型型为AA型)。

c.6812A>G变异信息如下：

综上分析可以看出，GPR98基因6812位点发生突变A>G与癫痫发生相关，该位点可以作为辅助诊断癫痫疾病的靶点，且含有该突变c.A6812G的核酸片段或相应的具有突变p.Q2271R的GPR98蛋白均可以作为辅助诊断癫痫疾病的生物标志物。相应的，用于检测含有具有突变c.A6812G的核酸片段的探针、引物或其他试剂以及检测具有突变p.Q2271R的GPR98蛋白的抗体等均可以用于制备辅助诊断癫痫疾病的制剂盒。

实施例2

本实施例提供了检测GPR98基因第6812位点突变的试剂盒，其包括：用于检测GPR98基因6812位点是否发生突变A6812G的引物，正向引物：TCCACTATAGGATGGTGCTTGG，反向引物：AGCATAGTTTGAACATTCTTGCAG；以及PCR扩增试剂：10×Buffer(含15mM Mg²⁺)、dNTP(2.5Mm)、高保真DNA聚合酶pfu DNA聚合酶(5U/μl)以及ddH₂O。

使用试剂盒的检测GPR98基因第6812位点是否发生突变A>G的方法，主要包括如下步骤：

(1)提取样本DNA，以此为模板，利用上述PCR反应试剂盒进行PCR反应。

(2)多重PCR产物检测：用琼脂糖凝胶对PCR扩增产物进行电泳检测PCR是否成功扩增，扩增片段小461bp。

(3)将PCR产物直接测序，将测序结果与正常GPR98基因序列比对，可判断待测样本的GPR98基因6812位点是否发生突变A>G。

以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

SEQUENCE LISTING

<110> 重庆医科大学附属第一医院

<120> 一种辅助癫痫诊断的标志物及其检测试剂盒

<160> 2

<170> PatentIn version 3.5

<210> 1

<211> 18921

<212> DNA

<213> 人工序列

<400> 1

atgtcggtgt tcctggggcc agggatgccc tctgcatctt tattagtaaa tcttctttca 60

gctttactca tcctatttgt gtttggagaa acagaaataa gatttactgg acaaactgaa 120

tttgttgtta atgaaacaag tacaacagtt attcgtctta tcattgaaag gataggagag 180

ccagcaaatg ttactgcaat tgtatcgctg tatggagagg acgctggtga cttttttgac 240

acatatgctg cagcttttat acctgccgga gaaacaaaca gaacagtgta catagcagta 300

tgtgatgatg acttaccaga gcctgacgaa acttttattt ttcacttaac attacagaaa 360

ccttcagcaa atgtgaagct tggatggcca aggactgtta ctgtgacaat attatcaaat 420

gacaatgcat ttggaattat ttcatttaat atgcttccct caatcgcagt gagtgagccc 480

aagggcagaa atgagtctat gcctcttact ctcatcaggg aaaagggaac ctatggaatg 540

gtcatggtga cttttgaggt agagggtggc ccaaatcccc ctgatgaaga tttgagtcca 600

gttaaaggaa atatcacctt tccccctggc agagcaacag taatttataa cttgacagta 660

ctcgatgacg aggtaccaga aaatgatgaa atatttttaa ttcaactgaa aagtgtagaa 720

ggaggagctg agattaacac ctctaggaat tccattgaga tcatcattaa gaaaaatgat 780

agtcccgtga gattccttca gagtatttat ttggttcctg aggaagacca catactcata 840

attccagtag ttcgtggaaa ggacaacaat ggaaatctga ttggatctga tgaatatgag 900

gtttcaatca gttatgctgt cacaactggg aattccacag cacatgccca gcaaaatctg 960

gacttcattg atcttcagcc aaacacaact gttgtttttc caccttttat tcatgaatct 1020

cacttgaaat ttcaaatagt tgatgacacc ataccggaga ttgctgaatc gtttcacatt 1080

atgttactaa aagatacctt acagggagat gctgtgctaa taagcccttc tgttgtacaa 1140

gtcaccatta agccaaatga taaaccttat ggagtccttt cattcaacag tgttttgttt 1200

gaaaggacag ttataattga tgaagataga atatcaagat atgaagaaat cacagtggtt 1260

agaaatggag gaacccatgg gaatgtctct gcgaattggg tgttgacacg gaacagcact 1320

gatccctcac cagtaacagc agatatcaga ccgagctctg gagttctcca ttttgcacaa 1380

gggcagatgt tggcaacaat tcctcttact gtggttgatg atgatcttcc agaagaggca 1440

gaagcttatc tacttcaaat tctgcctcat acaatacgag gaggtgcaga agtgagcgag 1500

ccagcggagc ttttgttcta cattcaggat agtgatgatg tctatggcct aataacattt 1560

tttcctatgg aaaaccagaa gattgaaagc agcccaggtg aacgatactt atccttgagt 1620

tttacaagac taggagggac taaaggagat gtgaggttgc tttattctgt actttacatt 1680

cctgctggag ctgtggaccc cttgcaagca aaagaaggca tcttaaatat atcaaggaga 1740

aatgacctca tttttccaga gcaaaaaact caagtcacta caaaattacc aataagaaat 1800

gatgcattcc ttcaaaatgg agctcacttt ctagtacagt tggaaactgt ggagttgtta 1860

aacataattc ctctaatccc acccataagc cctagatttg gggaaatctg caatatttct 1920

ttactggtta ctccagccat tgcaaatgga gaaattggct ttctcagcaa tcttccaatt 1980

attttgcatg aaccagaaga ttttgctgct gaagtggtat acattccctt acatcgggat 2040

ggaactgatg gccaggctac tgtctactgg agtttgaagc cctctggctt taattcaaaa 2100

gcagtgaccc cggatgatat aggccccttt aatggctctg ttttgttttt atctgggcaa 2160

agtgacacaa caatcaacat tactatcaaa ggtgatgaca taccggaaat gaatgaaact 2220

gtaacacttt ctctagacag ggttaacgtg gaaaaccaag tgctgaaatc tggatatact 2280

agccgtgacc taattatttt ggaaaatgat gaccctgggg gagtttttga attttctcct 2340

gcttccagag gaccctatgt tataaaagaa ggagaatctg tagagctcca catcatccga 2400

tcaagggggt cccttgttaa gcagtttcta cactaccgag tagagccaag agatagcaat 2460

gaattctatg gaaacacggg agtactagaa tttaaacctg gagaaaggga gatagtgatc 2520

accttgctag caagattgga tgggatacca gagttggatg aacactactg ggtggtcctc 2580

agcagccacg gagaacggga aagcaagttg ggaagtgcca ccattgtcaa tataacgatt 2640

ctgaaaaatg atgatcctca tggcattata gaatttgttt ctgatggtct aattgtgatg 2700

ataaatgaaa gcaaaggaga tgctatctat agtgctgttt atgatgtagt aagaaatcga 2760

ggcaactttg gtgatgttag tgtatcatgg gtggttagtc cagactttac acaagatgta 2820

tttcctgtac aagggactgt tgtctttgga gatcaggaat tttcaaaaaa tatcaccatt 2880

tactcccttc cagatgagat tccagaagaa atggaagaat ttaccgttat cctactgaat 2940

ggcactggag gagctaaagt gggaaataga acaactgcaa ctctgaggat tagaagaaat 3000

gatgacccca tttattttgc agaacctcgt gtagtgaggg ttcaggaagg tgagactgcc 3060

aactttacag ttctcagaaa tggatctgtt gatgtgactt gcatggtcca gtatgctacc 3120

aaggatggga aggctactgc aagagagaga gatttcattc ctgttgaaaa aggagaaacg 3180

ctcatttttg aggttggaag tagacagcag agcatatcca tatttgttaa tgaagatggt 3240

atcccggaaa cagatgagcc cttttatata atcctcttga attcaacagg tgatacagta 3300

gtatatcaat atggagtagc tacagtaata attgaagcta atgatgaccc aaatggcatt 3360

ttttctctgg agcccataga caaagcagtg gaagaaggaa agactaatgc attttggatt 3420

ttgaggcacc gaggatactt tggtagtgtt tctgtatctt ggcagctctt tcagaatgat 3480

tctgctttgc agcctgggca ggagttctat gaaacttcag gaactgttaa cttcatggat 3540

ggagaagaag caaaaccaat cattctccat gcttttccag ataaaattcc tgaattcaat 3600

gaattttatt tcctaaaact tgtaaacatt tcaggtggat ccccaggtcc tgggggccag 3660

ctagcagaaa ccaacctcca ggtgacagta atggttccat tcaatgatga tccctttgga 3720

gtttttatct tggatccaga gtgtttagag agagaagtgg cagaagatgt cctgtctgaa 3780

gatgatatgt cttatattac caacttcacc attttgaggc agcagggtgt gtttggtgat 3840

gtacaactgg gctgggaaat actgtccagt gagttccctg ctggtttgcc accaatgata 3900

gattttttac tggttggaat tttccccacc accgtgcatt tacaacagca catgcggcgt 3960

caccacagtg gaacggatgc tttgtacttt accggactag agggtgcatt tgggactgtt 4020

aatccaaaat accatccctc caggaataat acaattgcca actttacatt ctcagcttgg 4080

gtaatgccca atgccaatac gaatggattc attatagcga aggatgacgg taatggaagc 4140

atctactacg gggtaaaaat acaaacaaac gaatcccatg tgacactttc ccttcattat 4200

aaaaccttgg gttccaatgc tacatacatt gccaagacaa cagtcatgaa atatttagaa 4260

gaaagtgttt ggcttcatct actaattatc ctggaggatg gtataatcga attctacctg 4320

gatggaaatg caatgcccag gggaatcaag agtctgaaag gagaagccat tactgacggt 4380

cctgggatac tgagaattgg agcagggata aatggcaatg acagatttac aggtctgatg 4440

caggatgtga ggtcctatga gcggaaactg acgcttgaag aaatttatga acttcatgcc 4500

atgcccgcaa aaagtgattt acacccaatt tctggatatc tggagttcag acagggagaa 4560

actaacaaat cattcattat ttctgcaaga gatgacaatg acgaggaagg agaagaatta 4620

ttcattctta aactagtttc tgtatatgga ggagctcgta tttcggaaga aaatactact 4680

gcaagattaa caatacaaaa aagtgacaat gcaaatggct tgtttggttt cacaggagct 4740

tgtataccag agattgcaga ggagggatca accatttctt gtgtggttga gagaaccaga 4800

ggagctctgg attatgtgca tgttttttac accatttcac agattgaaac tgatggcatt 4860

aattaccttg ttgatgactt tgctaatgcc agtggaacta ttacattcct tccttggcag 4920

agatcagagg ttctgaatat atatgttctt gatgatgata ttcctgaact taatgagtat 4980

ttccgtgtga cattggtttc tgcaattcct ggagatggga agctaggctc aactcctacc 5040

agtggtgcaa gcatagatcc tgaaaaggaa acgactgata tcaccatcaa agctagtgat 5100

catccatatg gcttgctgca gttctccaca gggctgcctc ctcagcctaa ggacgcaatg 5160

accctgcctg caagcagcgt tccacatatc actgtggagg aggaagatgg agaaatcagg 5220

ttattggtca tccgtgcaca gggacttctg ggaagggtga ctgcggaatt tagaacagtg 5280

tccttgacag cattcagtcc tgaggattac cagaatgttg ctggcacatt agaatttcaa 5340

ccaggagaaa gatataaata cattttcata aacatcactg ataattctat tcctgaactg 5400

gaaaaatctt ttaaagttga gttgttaaac ttggaaggag gagtagctga actctttagg 5460

gttgatggaa gtggtagtgg tgatggggac atggaattct tccttccaac tattcacaaa 5520

cgtgccagtc taggagtggc ttcccaaatt ctagtgacaa ttgcagcctc tgaccacgct 5580

catggcgtat ttgaatttag ccctgagtca ctctttgtca gtggaactga accagaagat 5640

gggtatagca ctgttacatt aaatgttata agacatcatg gaactctgtc tccagtgact 5700

ttgcattgga acatagactc tgatcctgat ggtgatctcg ccttcacctc tggcaacatc 5760

acatttgaga ttgggcagac gagcgccaat atcactgtgg agatattgcc tgacgaagac 5820

ccagaactgg ataaggcatt ctctgtgtca gtcctcagtg tttccagtgg ttctttggga 5880

gctcatatta atgccacgtt aacagttttg gctagtgatg atccatatgg gatattcatt 5940

ttttctgaga aaaacagacc tgttaaagtt gaggaagcaa cccagaacat cacactatca 6000

ataataaggt tgaaaggcct catgggaaaa gtccttgtct catatgcaac actagatgat 6060

atggaaaaac caccttattt tccacctaat ttagcgagag caactcaagg aagagactat 6120

ataccagctt ctggatttgc tctttttgga gctaatcaga gtgaggcaac aatagctatt 6180

tcaattttgg atgatgatga gccagaaagg tccgaatctg tctttatcga actactcaac 6240

tctactttag tagcgaaagt acagagtcgt tcaattccaa attctccacg tcttgggcct 6300

aaggtagaaa ctattgcgca actaattatc attgccaatg atgatgcatt tggaactctt 6360

cagctctcag caccaattgt ccgagtggca gaaaatcatg ttggacccat tatcaatgtg 6420

actagaacag gaggagcatt tgcagatgtc tctgtgaagt ttaaagctgt gccaataact 6480

gcaatagctg gtgaagatta tagtatagct tcatcagatg tggtcttgct agaaggggaa 6540

accagtaaag ccgtgccaat atatgtcatt aatgatatct atcctgaact ggaagaatct 6600

tttcttgtgc aactgatgaa tgaaacaaca ggaggagcca gactaggggc tttaacagag 6660

gcagtcatta ttattgaggc ctctgatgac ccctatggat tatttggttt tcagattact 6720

aaacttattg tagaggaacc tgagtttaac tcagtgaagg taaacctgcc aataattcga 6780

aattctggga cactcggcaa tgttactgtt cggtgggttg ccaccattaa tggacagctt 6840

gctactggcg acctgcgagt tgtctcaggt aatgtgacct ttgcccctgg ggaaaccatt 6900

caaaccttgt tgttagaggt cctggctgac gacgttccgg agattgaaga ggttatccaa 6960

gtgcaactaa ctgatgcctc tggtggaggt actattgggt tagatcgaat tgcaaatatt 7020

attattcctg ccaatgatga tccttatggt acagtagcct ttgctcagat ggtttatcgt 7080

gttcaagagc ctctggaaag aagttcctgt gctaatataa ctgtcaggcg aagcggaggg 7140

cactttggtc ggctgttgtt gttctacagt acttccgaca ttgatgtagt ggctctggca 7200

atggaggaag gtcaagattt actgtcctac tatgaatctc caattcaagg ggtgcctgac 7260

ccactttgga gaacttggat gaatgtctct gccgtggggg agcccctgta tacctgtgcc 7320

actttgtgcc ttaaggaaca agcttgctca gcgttttcat ttttcagtgc ttctgagggt 7380

ccccagtgtt tctggatgac atcatggatc agcccagctg tcaacaattc agacttctgg 7440

acctacagga aaaacatgac cagggtagca tctcttttta gtggtcaggc tgtggctggg 7500

agtgactatg agcctgtgac aaggcaatgg gccataatgc aggaaggtga tgaattcgca 7560

aatctcacag tgtctattct tcctgatgat ttcccagaga tggatgagag ttttctaatt 7620

tctctccttg aagttcacct catgaacatt tcagccagtt tgaaaaatca gccaaccata 7680

ggacagccaa atatttctac agttgtcata gcactaaatg gtgatgcctt tggagtgttt 7740

gtgatctaca atattagtcc caatacttcc gaagatggct tatttgttga agttcaggag 7800

cagccccaaa ccttggtgga gctgatgata cacaggacag ggggcagctt aggtcaagtg 7860

gcagtcgaat ggcgtgttgt tggtggaaca gctactgaag gtttagattt tataggtgct 7920

ggagagattc tgacctttgc tgaaggtgaa accaaaaaga cagtcatttt aaccatcttg 7980

gatgactctg aaccagagga tgacgaaagt atcatagtta gtttggtgta cactgaaggt 8040

ggaagtagaa ttttgccaag ctccgacact gttagagtga acattttggc caatgacaat 8100

gtggcaggaa ttgttagctt tcagacagct tccagatctg tcataggtca tgaaggagaa 8160

attttacaat tccatgtgat aagaactttc cctggtcgag gaaatgttac tgttaactgg 8220

aaaattattg ggcaaaatct agaactcaat tttgctaact ttagcggaca acttttcttt 8280

cctgaggggt cgttgaatac aacattgttt gtgcatttgt tggatgacaa cattcctgag 8340

gagaaagaag tataccaagt cattctgtat gatgtcagga cacaaggagt tccaccagcc 8400

ggaatcgccc tgcttgatgc tcaaggatat gcagctgtcc tcacagtaga agccagtgat 8460

gaaccacatg gagttttaaa ttttgctctt tcatcaagat ttgtgttact acaagaggct 8520

aacataacaa ttcagctttt catcaacaga gaatttggat ctctaggagc tatcaatgtc 8580

acatatacca cggttcctgg aatgctgagt ctgaagaacc aaacagtagg aaacctagca 8640

gagccagaag ttgattttgt ccctatcatt ggctttctga ttttagaaga aggggaaaca 8700

gcagcagcca tcaacattac cattcttgag gatgatgtac cagagctaga agaatatttc 8760

ctggtgaatt taacttacgt tggacttacc atggctgctt caacttcatt tcctcccaga 8820

ctagattcag aaggtttgac tgcacaagtt attattgatg ccaatgatgg ggcccgaggt 8880

gtaattgaat ggcaacaaag caggtttgaa gtaaatgaaa cccatggaag tttaacattg 8940

gtagcccaga ggagcagaga acctcttggc catgtttcct tatttgtgta tgctcagaat 9000

ttggaagcac aagtggggct ggattatatc ttcaccccaa tgattcttca ttttgctgat 9060

ggagaaaggt ataaaaatgt caatatcatg attcttgatg atgacattcc agaaggagat 9120

gaaaaatttc agctgatttt aacaaatcct tctcctggac tagagctagg gaaaaataca 9180

atagccttaa ttattgtcct tgctaatgat gacggccctg gagttctatc atttaacaac 9240

agtgagcact ttttcctaag agagccaaca gctctctacg tccaggagag tgttgcagta 9300

ttgtacattg ttcgggaacc tgcacaagga ttgtttggaa cagtgacagt tcagttcatt 9360

gtgacagaag tgaattcctc aaatgaatct aaagatctga ctccttccaa aggctatatt 9420

gttttagaag aaggtgttcg attcaaggcc ctacaaatat ctgccatatt agacacggaa 9480

ccagaaatgg atgagtattt tgtttgcacc ttgtttaatc caactggagg tgctagacta 9540

ggggtgcatg ttcaaaccct gataacagtt ttgcaaaacc aggccccttt ggggctattc 9600

agtatctctg cagttgaaaa tagagccacc tccatagaca tcgaagaagc caataggacc 9660

gtgtatttaa atgtatctcg aactaatggc attgatttgg ctgtgagtgt gcagtgggag 9720

acagtatctg aaacagcctt tggcatgagg ggaatggatg ttgtgttttc cgtatttcaa 9780

agttttttgg atgaatcagc ttctggctgg tgtttcttta ctttggaaaa tttaatatat 9840

ggtataatgt taagaaaatc atctgttact gtttaccgat ggcaggggat ttttattcca 9900

gttgaggatt taaatataga aaatcctaaa acttgtgagg cctttaatat tggtttttct 9960

ccctactttg tgattactca tgaagaaaga aatgaagaaa agccttctct taacagtgtg 10020

tttacattca catctggatt taaattattc ctggtacaaa caatcattat tctggaaagt 10080

tctcaagtaa gatattttac ttcagacagc caagattatt taatcattgc aagtcaaaga 10140

gatgattccg aattaactca ggtcttcagg tggaatggag gaagcttcgt gttgcatcaa 10200

aaactccctg tccgaggtgt gctgaccgtg gccttgttca acaagggagg ctctgtgttc 10260

ttagccattt cccaggctaa tgccaggcta aactcccttt tattcagatg gtctggcagt 10320

gggtttatta actttcaaga ggtgcctgtc agtgggacaa cagaagttga ggctttgtct 10380

tcagccaatg atatttacct aatatttgcc gaaaatgtct ttctaggaga tcagaattca 10440

attgatattt tcatctggga gatgggacag tcttccttca ggtattttca gtctgtagat 10500

tttgctgctg ttaacagaat ccactccttc acaccagcct caggaatagc ccacatactt 10560

cttattggcc aagatatgtc tgctctttac tgctggaatt cggagcgtaa tcaattctct 10620

tttgttctgg aagtaccttc tgcttatgat gtggcttctg ttacagtaaa gtcccttaat 10680

tcaagcaaga atttaatagc tctagtggga gctcattcac atatatatga gctagcctac 10740

atttccagcc attctgactt tattcctagt tcaggtgaac tgatatttga acctggtgag 10800

agagaagcta caatagcagt aaatatcctt gatgatacag ttccagaaaa agaagaatcc 10860

ttcaaagttc aacttaaaaa tcccaaagga ggagcagaga ttggcattaa tgattctgta 10920

acaataacca ttctgtctaa tgatgatgcc tatggaattg ttgcatttgc tcagaattca 10980

ttatataagc aagtggaaga aatggagcaa gatagcctag taaccttgaa cgttgaacgc 11040

ttaaaaggaa catatggccg tataaccata gcatgggaag ctgatggaag tattagtgat 11100

atatttccta cctcaggagt gattttattt actgaaggcc aggtactgtc aacaatcact 11160

ctaactattc ttgctgataa tataccagag ttatcagagg ttgtgattgt aaccctcacc 11220

cgtatcacca cagaaggggt tgaggactca tacaaaggtg ctactattga tcaggacaga 11280

agcaagtctg ttataacaac tttgcccaat gactcacctt ttggcttggt gggctggcgt 11340

gctgcgtctg tcttcattag agtagcagag cctaaagaaa acaccaccac tcttcagtta 11400

caaatagctc gagataaagg actacttggg gatattgcca ttcacttgag agctcaaccc 11460

aatttcttac tgcatgtcga taatcaagct actgagaatg aagattatgt attgcaagaa 11520

acaataataa taatgaaaga aaacataaaa gaagctcatg ccgaagtttc cattttgccg 11580

gatgaccttc ctgaattgga ggaaggattt attgtcacta tcactgaggt gaacctggtg 11640

aactctgact tctctacagg acagccaagt gtgcggaggc ccggaatgga aatagctgag 11700

ataatgatag aagaaaatga cgatcccaga ggaattttta tgtttcatgt tactagaggc 11760

gctggggaag ttattactgc ctatgaggtg cctccaccct tgaacgttct tcaagttcct 11820

gtagtccggc tggctggaag ctttggggca gtaaatgttt attggaaagc atcaccagac 11880

agtgctggcc tggaagactt taaaccatct catgggattc ttgaatttgc agataaacag 11940

gttactgcaa tgatagaaat caccataatt gatgatgctg aatttgaatt gacagagacg 12000

ttcaatattt ccttgatcag tgttgctgga ggtggcagac ttggtgatga tgttgtggta 12060

actgttgtta ttccacaaaa tgattctcca tttggagtat ttggatttga agaaaagact 12120

gtaatgattg atgaatccct ttcatccgat gaccctgatt catatgtgac attgacggtt 12180

gtccggtccc caggaggaaa aggaaccgtc cgacttgagt ggaccataga tgagaaggct 12240

aaacataacc ttagtccttt gaatgggacc cttcattttg atgagactga gtcccagaag 12300

accattgtgt tgcacacact tcaagacaca gtgttggagg aggacaggcg tttcaccatt 12360

cagctgatat caattgatga ggtagaaata tctccagtaa aaggtagtgc atcaataatt 12420

attcggggtg ataagcgagc atcaggagaa gttgggatag ctccgtcatc taggcacatc 12480

ctcattgggg aaccctcagc aaaatataat ggtaccgcta ttatcagcct tgttcgaggc 12540

ccagggattt tgggggaggt cacagtgttc tggaggatat tccctccttc cgtgggggaa 12600

tttgctgaaa catcaggaaa actgacaatg cgagacgaac agtctgcagt cattgtagta 12660

atacaggctt tgaacgatga cattcccgag gaaaaaagct tctatgagtt tcagctcact 12720

gcagtcagtg agggaggagt tctgagtgaa tccagcagca ctgccaacat cacggtggtg 12780

gccagcgact ctccctatgg ccgatttgcc ttttcacatg agcaacttcg agtgtcagaa 12840

gcacagaggg ttaacatcac aatcatccgt tccagtggag attttggcca tgtgcgactc 12900

tggtacaaga cgatgagcgg gacagcggaa gcaggcttgg attttgttcc tgcagcaggg 12960

gagctcctct ttgaagcagg ggagatgagg aaaagtctgc atgttgaaat ccttgatgat 13020

gactatcctg aaggcccaga ggaattttct ctaacaatta caaaggtgga actccaggga 13080

agagggtatg attttaccat tcaagaaaat ggacttcaga tagatcaacc tcctgaaata 13140

ggaaacatct ccattgttcg catcataata atgaaaaatg ataacgcaga aggcatcatt 13200

gaatttgacc caaagtatac tgccttcgaa gtggaggaag atgttgggct gatcatgatc 13260

ccagtggtga ggctacatgg aacttatggc tatgtgacag ctgatttcat ctctcagagc 13320

tcctctgcca gtcccggagg tgttgattac attttgcatg gcagtacagt cacctttcag 13380

catgggcaaa acttaagttt tataaatatc tccatcattg atgacaatga aagtgaattt 13440

gaggagccca ttgaaattct actcactgga gctactggag gagcggtcct tgggcgccac 13500

ctagtgagca gaatcataat agctaagagt gactctccct ttggagttat aaggtttctc 13560

aatcaaagca aaatttctat tgctaatccc aattccacaa tgattttatc actggtgctg 13620

gagcggactg gaggactctt gggagagatt caggtgaact gggagacagt aggacccaac 13680

tctcaagaag ccttactgcc acagaataga gacattgcag acccagtgag cgggttgttc 13740

tattttggag aaggagaagg aggagtgaga accataattc tgacaatcta tcctcatgaa 13800

gaaattgaag ttgaagagac attcattatt aaacttcatc ttgtgaaagg agaagctaaa 13860

ttagactcca gagctaaaga tgttacatta accatacaag agtttggtga cccaaatgga 13920

gttgttcagt ttgctcctga aactttgtct aagaagactt attcagagcc tctggctctg 13980

gaagggcccc tgctcattac cttctttgtc agaagagtca agggcacctt tggagagatt 14040

atggtttact gggaattaag tagtgagttt gacattactg aagactttct ttccaccagt 14100

ggatttttca ccattgctga tggagagagt gaagctagct ttgatgttca tttgctacca 14160

gatgaggtac ctgagataga ggaagattat gtgatccagc ttgtttctgt agagggagga 14220

gccgaactgg atctggagaa gagtatcaca tggttctctg tttatgcaaa tgatgaccca 14280

catggagtat ttgccctgta ttcggatcgc cagtcaatac ttattgggca gaaccttatt 14340

agatccatcc aaattaacat aacccggctt gctggaacat ttggagatgt ggctgttggg 14400

cttcgaatat catcggatca taaagaacag ccgattgtta ccgaaaatgc agagaggcag 14460

ctggtggtca aagatggtgc cacatataaa gtggacgtgg tgccaataaa gaatcaggtc 14520

ttcctatcac tgggctctaa tttcactttg caactggtga ctgtgatgct tgtcggtgga 14580

cgtttctatg gaatgccaac aattcttcag gaagcaaaat ctgctgtcct tccagtctct 14640

gagaaagctg ccaattctca ggtcggattt gaatccactg cttttcaact catgaacatc 14700

actgctggca caagccacgt tatgatttct aggagaggca catatggagc tctctcggtt 14760

gcctggacca ctggatatgc tcctgggtta gaaattcctg aattcattgt tgttggcaac 14820

atgaccccaa cactggggag cctttcattt tcccacggtg aacaaaggaa aggagttttc 14880

ctgtggacgt ttcctagccc tggttggcca gaggcctttg ttcttcacct atcaggagtg 14940

cagagcagtg ctcctggcgg agctcaactc cgatcaggtt tcattgttgc tgaaattgaa 15000

ccaatgggcg tcttccaatt ttccactagc tcaagaaata tcatagtgtc agaagataca 15060

cagatgatca gattacatgt acaaagacta tttgggttcc acagcgatct tattaaagtt 15120

tcttatcaga ccactgcagg aagcgccaag ccactggaag attttgagcc tgttcagaat 15180

ggggaactgt tttttcaaaa attccaaact gaggttgatt ttgaaataac cattattaat 15240

gatcagcttt ctgagataga agaatttttt tacattaacc ttacttcagt agaaattagg 15300

ggattacaaa agtttgatgt taattggagc ccacgcctga atctagattt cagtgttgca 15360

gtgattacaa tattggataa tgatgacctg gcaggaatgg atatttcctt ccccgagaca 15420

actgtggctg tagcagttga cacaactctc attcctgtag aaactgaatc caccacatac 15480

ctcagcacaa gcaagacgac taccattctg cagccaacca acgtggttgc cattgttact 15540

gaggcaactg gtgtatctgc catccctgag aaacttgtca cccttcatgg cacacctgct 15600

gtgtctgaaa agcctgatgt ggccactgta actgccaatg tttccattca tggaacattc 15660

agccttgggc catccattgt ttatattgaa gaggagatga agaatggcac attcaacact 15720

gcagaagttc ttatccgaag aactggtggg tttactggca atgtcagcat aacagttaaa 15780

actttcggtg aaagatgtgc tcagatggaa ccaaatgcat tgccctttcg tggtatctat 15840

gggatttcca acctaacatg ggcagttgaa gaagaagact ttgaagaaca aactcttacc 15900

cttatattcc tagatggaga aagagaacgt aaagtatcag ttcaaatttt ggatgatgat 15960

gagcctgagg ggcaggaatt cttctacgtg tttctcacaa accctcaagg gggagcacag 16020

attgtggagg agaaggatga tactggattt gcagcttttg ccatggttat tattacaggg 16080

agtgaccttc acaatggcat cataggattc agtgaggagt cccagagtgg actagaactc 16140

agggaaggag ctgttatgag aagattgcac cttattgtca caagacagcc aaacagggcc 16200

tttgaagatg tcaaggtctt ttggcgagtc acacttaaca aaacagtcgt cgtgctccag 16260

aaggatgggg taaacctggt ggaggaactt cagtctgtgt cagggaccac aacctgtaca 16320

atgggtcaaa caaaatgctt tatcagcatt gaactcaaac cagaaaaggt accacaggtt 16380

gaagtgtatt tttttgtgga actatatgaa gctactgctg gagcagcaat aaacaacagt 16440

gccagattcg cacagattaa aatcttagaa agtgatgaat ctcaaagcct tgtgtatttt 16500

tctgtgggtt ctcggctggc agtggctcac aagaaggcca ctttaatcag tctgcaggtg 16560

gccagagatt ctgggacagg actaatgatg tctgttaact ttagtaccca ggagttgagg 16620

agtgctgaaa caattggtcg taccatcata tctccagcta tttctggaaa ggattttgtg 16680

ataactgaag gcacattggt ctttgaacct ggccagagaa gcactgtatt ggatgtcatc 16740

ctaacgccag agacaggatc tttaaattca tttcctaaac gcttccagat tgtccttttt 16800

gacccaaaag gtggtgccag aattgataaa gtgtatggga ctgccaacat cactcttgtc 16860

tcagatgcag attcgcaggc catttggggg cttgcagatc agctacatca gcctgtgaat 16920

gatgatattc tcaacagagt gctccatacc atcagcatga aagtggccac agaaaacaca 16980

gatgaacaac tcagtgccat gatgcattta atagaaaaga taactactga aggaaaaatt 17040

caagctttca gtgttgccag ccgaactctt ttctatgaga ttctttgttc tcttattaac 17100

ccaaagcgca aggacactag gggattcagt cactttgctg aagtgactga gaattttgcc 17160

ttttctctgc tgactaatgt tacttgcggc tctcctggtg aaaaaagcaa aaccatcctt 17220

gatagttgcc catatttgtc aatattggct cttcactggt atcctcagca aatcaatgga 17280

cacaagtttg aaggaaagga aggagattac attcgaattc cagagaggct actggatgtc 17340

caggatgcag aaataatggc tgggaaaagt acatgtaaat tagtccagtt tacagagtat 17400

agcagccaac agtggtttat aagtggaaac aatcttccta ccctaaaaaa taaggtatta 17460

tctttgagtg tgaaaggtca gagttcacaa ctcctgacta atgacaatga ggttctctac 17520

aggatttatg ctgctgagcc tagaattatt cctcagacat ctctgtgtct cctttggaat 17580

caggctgctg caagctggtt gtctgacagt cagttttgca aagtggttga ggaaactgca 17640

gactatgtgg aatgtgcctg ttcacacatg tctgtgtatg ctgtctatgc tcggactgac 17700

aacttgtctt catacaatga agccttcttc acttctggat ttatatgtat ctcaggtctt 17760

tgcttggctg ttctttccca tatcttctgt gccaggtact ccatgtttgc agctaaactt 17820

ctgactcaca tgatggcagc cagcttaggt acacagattc tgtttctggc gtctgcatac 17880

gcaagtcccc aactcgctga ggagagctgt tcagctatgg ctgctgtcac acattacctg 17940

tatctttgcc agtttagctg gatgctcatt cagtctgtga atttctggta cgtgctggtg 18000

atgaatgatg agcacacaga gaggcgatat ctgctgtttt tccttctgag ttggggacta 18060

ccagcttttg tggtgattct cctcatagtt attttgaaag gaatctatca tcagagcatg 18120

tcacagatct atggactcat tcatggtgac ctgtgtttta ttccaaacgt ctatgctgct 18180

ttgttcactg cagctcttgt tcctttgacg tgcctcgtgg tggtgttcgt ggtgttcatc 18240

catgcctacc aggtgaagcc acagtggaaa gcatatgatg atgtcttcag aggaaggaca 18300

aatgctgcag aaattccact gattttatat ctctttgctc tgatttccgt gacatggctt 18360

tggggaggac tacacatggc ctacagacac ttctggatgt tggttctctt tgtcattttc 18420

aacagtctgc agggacttta tgttttcatg gtttatttca ttttacacaa ccaaatgtgt 18480

tgccctatga aggccagtta cactgtggaa atgaatgggc atcctggacc cagcacagcc 18540

tttttcacgc ccgggagtgg aatgcctcct gctggagggg aaatcagcaa gtccacccag 18600

aatctcatcg gtgctatgga ggaggtgcca cctgactggg agagagcatc cttccaacag 18660

ggcagtcagg ccagccctga tttaaagcca agtccacaaa atggagccac gttcccgtcc 18720

tctggaggat atggccaggg gtcactgata gccgatgagg agtcccagga gtttgatgat 18780

ttaatatttg cattaaaaac tggtgctggt ctcagtgtca gtgataatga atctggtcaa 18840

ggcagccagg aggggggcac cttgactgac tcccagatcg tggagctcag gaggataccc 18900

atcgccgaca ctcacctgta g 18921

<210> 2

<211> 6306

<212> PRT

<213> 人工序列

<400> 2

Met Ser Val Phe Leu Gly Pro Gly Met Pro Ser Ala Ser Leu Leu Val

1 5 10 15

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

20 25 30

Ile Arg Phe Thr Gly Gln Thr Glu Phe Val Val Asn Glu Thr Ser Thr

35 40 45

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

50 55 60

Thr Ala Ile Val Ser Leu Tyr Gly Glu Asp Ala Gly Asp Phe Phe Asp

65 70 75 80

Thr Tyr Ala Ala Ala Phe Ile Pro Ala Gly Glu Thr Asn Arg Thr Val

85 90 95

Tyr Ile Ala Val Cys Asp Asp Asp Leu Pro Glu Pro Asp Glu Thr Phe

100 105 110

Ile Phe His Leu Thr Leu Gln Lys Pro Ser Ala Asn Val Lys Leu Gly

115 120 125

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

130 135 140

Gly Ile Ile Ser Phe Asn Met Leu Pro Ser Ile Ala Val Ser Glu Pro

145 150 155 160

Lys Gly Arg Asn Glu Ser Met Pro Leu Thr Leu Ile Arg Glu Lys Gly

165 170 175

Thr Tyr Gly Met Val Met Val Thr Phe Glu Val Glu Gly Gly Pro Asn

180 185 190

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

195 200 205

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

210 215 220

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

225 230 235 240

Gly Gly Ala Glu Ile Asn Thr Ser Arg Asn Ser Ile Glu Ile Ile Ile

245 250 255

Lys Lys Asn Asp Ser Pro Val Arg Phe Leu Gln Ser Ile Tyr Leu Val

260 265 270

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

275 280 285

Asn Asn Gly Asn Leu Ile Gly Ser Asp Glu Tyr Glu Val Ser Ile Ser

290 295 300

Tyr Ala Val Thr Thr Gly Asn Ser Thr Ala His Ala Gln Gln Asn Leu

305 310 315 320

Asp Phe Ile Asp Leu Gln Pro Asn Thr Thr Val Val Phe Pro Pro Phe

325 330 335

Ile His Glu Ser His Leu Lys Phe Gln Ile Val Asp Asp Thr Ile Pro

340 345 350

Glu Ile Ala Glu Ser Phe His Ile Met Leu Leu Lys Asp Thr Leu Gln

355 360 365

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

370 375 380

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

385 390 395 400

Glu Arg Thr Val Ile Ile Asp Glu Asp Arg Ile Ser Arg Tyr Glu Glu

405 410 415

Ile Thr Val Val Arg Asn Gly Gly Thr His Gly Asn Val Ser Ala Asn

420 425 430

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

435 440 445

Ile Arg Pro Ser Ser Gly Val Leu His Phe Ala Gln Gly Gln Met Leu

450 455 460

Ala Thr Ile Pro Leu Thr Val Val Asp Asp Asp Leu Pro Glu Glu Ala

465 470 475 480

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

485 490 495

Glu Val Ser Glu Pro Ala Glu Leu Leu Phe Tyr Ile Gln Asp Ser Asp

500 505 510

Asp Val Tyr Gly Leu Ile Thr Phe Phe Pro Met Glu Asn Gln Lys Ile

515 520 525

Glu Ser Ser Pro Gly Glu Arg Tyr Leu Ser Leu Ser Phe Thr Arg Leu

530 535 540

Gly Gly Thr Lys Gly Asp Val Arg Leu Leu Tyr Ser Val Leu Tyr Ile

545 550 555 560

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

565 570 575

Ile Ser Arg Arg Asn Asp Leu Ile Phe Pro Glu Gln Lys Thr Gln Val

580 585 590

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

595 600 605

His Phe Leu Val Gln Leu Glu Thr Val Glu Leu Leu Asn Ile Ile Pro

610 615 620

Leu Ile Pro Pro Ile Ser Pro Arg Phe Gly Glu Ile Cys Asn Ile Ser

625 630 635 640

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

645 650 655

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

660 665 670

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

675 680 685

Tyr Trp Ser Leu Lys Pro Ser Gly Phe Asn Ser Lys Ala Val Thr Pro

690 695 700

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

705 710 715 720

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

725 730 735

Met Asn Glu Thr Val Thr Leu Ser Leu Asp Arg Val Asn Val Glu Asn

740 745 750

Gln Val Leu Lys Ser Gly Tyr Thr Ser Arg Asp Leu Ile Ile Leu Glu

755 760 765

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

770 775 780

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

785 790 795 800

Ser Arg Gly Ser Leu Val Lys Gln Phe Leu His Tyr Arg Val Glu Pro

805 810 815

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

820 825 830

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

835 840 845

Ile Pro Glu Leu Asp Glu His Tyr Trp Val Val Leu Ser Ser His Gly

850 855 860

Glu Arg Glu Ser Lys Leu Gly Ser Ala Thr Ile Val Asn Ile Thr Ile

865 870 875 880

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

885 890 895

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

900 905 910

Val Tyr Asp Val Val Arg Asn Arg Gly Asn Phe Gly Asp Val Ser Val

915 920 925

Ser Trp Val Val Ser Pro Asp Phe Thr Gln Asp Val Phe Pro Val Gln

930 935 940

Gly Thr Val Val Phe Gly Asp Gln Glu Phe Ser Lys Asn Ile Thr Ile

945 950 955 960

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

965 970 975

Ile Leu Leu Asn Gly Thr Gly Gly Ala Lys Val Gly Asn Arg Thr Thr

980 985 990

Ala Thr Leu Arg Ile Arg Arg Asn Asp Asp Pro Ile Tyr Phe Ala Glu

995 1000 1005

Pro Arg Val Val Arg Val Gln Glu Gly Glu Thr Ala Asn Phe Thr

1010 1015 1020

Val Leu Arg Asn Gly Ser Val Asp Val Thr Cys Met Val Gln Tyr

1025 1030 1035

Ala Thr Lys Asp Gly Lys Ala Thr Ala Arg Glu Arg Asp Phe Ile

1040 1045 1050

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

1055 1060 1065

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

1070 1075 1080

Thr Asp Glu Pro Phe Tyr Ile Ile Leu Leu Asn Ser Thr Gly Asp

1085 1090 1095

Thr Val Val Tyr Gln Tyr Gly Val Ala Thr Val Ile Ile Glu Ala

1100 1105 1110

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

1115 1120 1125

Ala Val Glu Glu Gly Lys Thr Asn Ala Phe Trp Ile Leu Arg His

1130 1135 1140

Arg Gly Tyr Phe Gly Ser Val Ser Val Ser Trp Gln Leu Phe Gln

1145 1150 1155

Asn Asp Ser Ala Leu Gln Pro Gly Gln Glu Phe Tyr Glu Thr Ser

1160 1165 1170

Gly Thr Val Asn Phe Met Asp Gly Glu Glu Ala Lys Pro Ile Ile

1175 1180 1185

Leu His Ala Phe Pro Asp Lys Ile Pro Glu Phe Asn Glu Phe Tyr

1190 1195 1200

Phe Leu Lys Leu Val Asn Ile Ser Gly Gly Ser Pro Gly Pro Gly

1205 1210 1215

Gly Gln Leu Ala Glu Thr Asn Leu Gln Val Thr Val Met Val Pro

1220 1225 1230

Phe Asn Asp Asp Pro Phe Gly Val Phe Ile Leu Asp Pro Glu Cys

1235 1240 1245

Leu Glu Arg Glu Val Ala Glu Asp Val Leu Ser Glu Asp Asp Met

1250 1255 1260

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

1265 1270 1275

Gly Asp Val Gln Leu Gly Trp Glu Ile Leu Ser Ser Glu Phe Pro

1280 1285 1290

Ala Gly Leu Pro Pro Met Ile Asp Phe Leu Leu Val Gly Ile Phe

1295 1300 1305

Pro Thr Thr Val His Leu Gln Gln His Met Arg Arg His His Ser

1310 1315 1320

Gly Thr Asp Ala Leu Tyr Phe Thr Gly Leu Glu Gly Ala Phe Gly

1325 1330 1335

Thr Val Asn Pro Lys Tyr His Pro Ser Arg Asn Asn Thr Ile Ala

1340 1345 1350

Asn Phe Thr Phe Ser Ala Trp Val Met Pro Asn Ala Asn Thr Asn

1355 1360 1365

Gly Phe Ile Ile Ala Lys Asp Asp Gly Asn Gly Ser Ile Tyr Tyr

1370 1375 1380

Gly Val Lys Ile Gln Thr Asn Glu Ser His Val Thr Leu Ser Leu

1385 1390 1395

His Tyr Lys Thr Leu Gly Ser Asn Ala Thr Tyr Ile Ala Lys Thr

1400 1405 1410

Thr Val Met Lys Tyr Leu Glu Glu Ser Val Trp Leu His Leu Leu

1415 1420 1425

Ile Ile Leu Glu Asp Gly Ile Ile Glu Phe Tyr Leu Asp Gly Asn

1430 1435 1440

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

1445 1450 1455

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

1460 1465 1470

Asp Arg Phe Thr Gly Leu Met Gln Asp Val Arg Ser Tyr Glu Arg

1475 1480 1485

Lys Leu Thr Leu Glu Glu Ile Tyr Glu Leu His Ala Met Pro Ala

1490 1495 1500

Lys Ser Asp Leu His Pro Ile Ser Gly Tyr Leu Glu Phe Arg Gln

1505 1510 1515

Gly Glu Thr Asn Lys Ser Phe Ile Ile Ser Ala Arg Asp Asp Asn

1520 1525 1530

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

1535 1540 1545

Tyr Gly Gly Ala Arg Ile Ser Glu Glu Asn Thr Thr Ala Arg Leu

1550 1555 1560

Thr Ile Gln Lys Ser Asp Asn Ala Asn Gly Leu Phe Gly Phe Thr

1565 1570 1575

Gly Ala Cys Ile Pro Glu Ile Ala Glu Glu Gly Ser Thr Ile Ser

1580 1585 1590

Cys Val Val Glu Arg Thr Arg Gly Ala Leu Asp Tyr Val His Val

1595 1600 1605

Phe Tyr Thr Ile Ser Gln Ile Glu Thr Asp Gly Ile Asn Tyr Leu

1610 1615 1620

Val Asp Asp Phe Ala Asn Ala Ser Gly Thr Ile Thr Phe Leu Pro

1625 1630 1635

Trp Gln Arg Ser Glu Val Leu Asn Ile Tyr Val Leu Asp Asp Asp

1640 1645 1650

Ile Pro Glu Leu Asn Glu Tyr Phe Arg Val Thr Leu Val Ser Ala

1655 1660 1665

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

1670 1675 1680

Ser Ile Asp Pro Glu Lys Glu Thr Thr Asp Ile Thr Ile Lys Ala

1685 1690 1695

Ser Asp His Pro Tyr Gly Leu Leu Gln Phe Ser Thr Gly Leu Pro

1700 1705 1710

Pro Gln Pro Lys Asp Ala Met Thr Leu Pro Ala Ser Ser Val Pro

1715 1720 1725

His Ile Thr Val Glu Glu Glu Asp Gly Glu Ile Arg Leu Leu Val

1730 1735 1740

Ile Arg Ala Gln Gly Leu Leu Gly Arg Val Thr Ala Glu Phe Arg

1745 1750 1755

Thr Val Ser Leu Thr Ala Phe Ser Pro Glu Asp Tyr Gln Asn Val

1760 1765 1770

Ala Gly Thr Leu Glu Phe Gln Pro Gly Glu Arg Tyr Lys Tyr Ile

1775 1780 1785

Phe Ile Asn Ile Thr Asp Asn Ser Ile Pro Glu Leu Glu Lys Ser

1790 1795 1800

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

1805 1810 1815

Phe Arg Val Asp Gly Ser Gly Ser Gly Asp Gly Asp Met Glu Phe

1820 1825 1830

Phe Leu Pro Thr Ile His Lys Arg Ala Ser Leu Gly Val Ala Ser

1835 1840 1845

Gln Ile Leu Val Thr Ile Ala Ala Ser Asp His Ala His Gly Val

1850 1855 1860

Phe Glu Phe Ser Pro Glu Ser Leu Phe Val Ser Gly Thr Glu Pro

1865 1870 1875

Glu Asp Gly Tyr Ser Thr Val Thr Leu Asn Val Ile Arg His His

1880 1885 1890

Gly Thr Leu Ser Pro Val Thr Leu His Trp Asn Ile Asp Ser Asp

1895 1900 1905

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

1910 1915 1920

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

1925 1930 1935

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

1940 1945 1950

Val Ser Ser Gly Ser Leu Gly Ala His Ile Asn Ala Thr Leu Thr

1955 1960 1965

Val Leu Ala Ser Asp Asp Pro Tyr Gly Ile Phe Ile Phe Ser Glu

1970 1975 1980

Lys Asn Arg Pro Val Lys Val Glu Glu Ala Thr Gln Asn Ile Thr

1985 1990 1995

Leu Ser Ile Ile Arg Leu Lys Gly Leu Met Gly Lys Val Leu Val

2000 2005 2010

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

2015 2020 2025

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

2030 2035 2040

Ser Gly Phe Ala Leu Phe Gly Ala Asn Gln Ser Glu Ala Thr Ile

2045 2050 2055

Ala Ile Ser Ile Leu Asp Asp Asp Glu Pro Glu Arg Ser Glu Ser

2060 2065 2070

Val Phe Ile Glu Leu Leu Asn Ser Thr Leu Val Ala Lys Val Gln

2075 2080 2085

Ser Arg Ser Ile Pro Asn Ser Pro Arg Leu Gly Pro Lys Val Glu

2090 2095 2100

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

2105 2110 2115

Thr Leu Gln Leu Ser Ala Pro Ile Val Arg Val Ala Glu Asn His

2120 2125 2130

Val Gly Pro Ile Ile Asn Val Thr Arg Thr Gly Gly Ala Phe Ala

2135 2140 2145

Asp Val Ser Val Lys Phe Lys Ala Val Pro Ile Thr Ala Ile Ala

2150 2155 2160

Gly Glu Asp Tyr Ser Ile Ala Ser Ser Asp Val Val Leu Leu Glu

2165 2170 2175

Gly Glu Thr Ser Lys Ala Val Pro Ile Tyr Val Ile Asn Asp Ile

2180 2185 2190

Tyr Pro Glu Leu Glu Glu Ser Phe Leu Val Gln Leu Met Asn Glu

2195 2200 2205

Thr Thr Gly Gly Ala Arg Leu Gly Ala Leu Thr Glu Ala Val Ile

2210 2215 2220

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

2225 2230 2235

Ile Thr Lys Leu Ile Val Glu Glu Pro Glu Phe Asn Ser Val Lys

2240 2245 2250

Val Asn Leu Pro Ile Ile Arg Asn Ser Gly Thr Leu Gly Asn Val

2255 2260 2265

Thr Val Arg Trp Val Ala Thr Ile Asn Gly Gln Leu Ala Thr Gly

2270 2275 2280

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

2285 2290 2295

Thr Ile Gln Thr Leu Leu Leu Glu Val Leu Ala Asp Asp Val Pro

2300 2305 2310

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

2315 2320 2325

Gly Gly Thr Ile Gly Leu Asp Arg Ile Ala Asn Ile Ile Ile Pro

2330 2335 2340

Ala Asn Asp Asp Pro Tyr Gly Thr Val Ala Phe Ala Gln Met Val

2345 2350 2355

Tyr Arg Val Gln Glu Pro Leu Glu Arg Ser Ser Cys Ala Asn Ile

2360 2365 2370

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

2375 2380 2385

Tyr Ser Thr Ser Asp Ile Asp Val Val Ala Leu Ala Met Glu Glu

2390 2395 2400

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

2405 2410 2415

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

2420 2425 2430

Glu Pro Leu Tyr Thr Cys Ala Thr Leu Cys Leu Lys Glu Gln Ala

2435 2440 2445

Cys Ser Ala Phe Ser Phe Phe Ser Ala Ser Glu Gly Pro Gln Cys

2450 2455 2460

Phe Trp Met Thr Ser Trp Ile Ser Pro Ala Val Asn Asn Ser Asp

2465 2470 2475

Phe Trp Thr Tyr Arg Lys Asn Met Thr Arg Val Ala Ser Leu Phe

2480 2485 2490

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

2495 2500 2505

Gln Trp Ala Ile Met Gln Glu Gly Asp Glu Phe Ala Asn Leu Thr

2510 2515 2520

Val Ser Ile Leu Pro Asp Asp Phe Pro Glu Met Asp Glu Ser Phe

2525 2530 2535

Leu Ile Ser Leu Leu Glu Val His Leu Met Asn Ile Ser Ala Ser

2540 2545 2550

Leu Lys Asn Gln Pro Thr Ile Gly Gln Pro Asn Ile Ser Thr Val

2555 2560 2565

Val Ile Ala Leu Asn Gly Asp Ala Phe Gly Val Phe Val Ile Tyr

2570 2575 2580

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

2585 2590 2595

Gln Glu Gln Pro Gln Thr Leu Val Glu Leu Met Ile His Arg Thr

2600 2605 2610

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

2615 2620 2625

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

2630 2635 2640

Leu Thr Phe Ala Glu Gly Glu Thr Lys Lys Thr Val Ile Leu Thr

2645 2650 2655

Ile Leu Asp Asp Ser Glu Pro Glu Asp Asp Glu Ser Ile Ile Val

2660 2665 2670

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

2675 2680 2685

Asp Thr Val Arg Val Asn Ile Leu Ala Asn Asp Asn Val Ala Gly

2690 2695 2700

Ile Val Ser Phe Gln Thr Ala Ser Arg Ser Val Ile Gly His Glu

2705 2710 2715

Gly Glu Ile Leu Gln Phe His Val Ile Arg Thr Phe Pro Gly Arg

2720 2725 2730

Gly Asn Val Thr Val Asn Trp Lys Ile Ile Gly Gln Asn Leu Glu

2735 2740 2745

Leu Asn Phe Ala Asn Phe Ser Gly Gln Leu Phe Phe Pro Glu Gly

2750 2755 2760

Ser Leu Asn Thr Thr Leu Phe Val His Leu Leu Asp Asp Asn Ile

2765 2770 2775

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

2780 2785 2790

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

2795 2800 2805

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

2810 2815 2820

Gly Val Leu Asn Phe Ala Leu Ser Ser Arg Phe Val Leu Leu Gln

2825 2830 2835

Glu Ala Asn Ile Thr Ile Gln Leu Phe Ile Asn Arg Glu Phe Gly

2840 2845 2850

Ser Leu Gly Ala Ile Asn Val Thr Tyr Thr Thr Val Pro Gly Met

2855 2860 2865

Leu Ser Leu Lys Asn Gln Thr Val Gly Asn Leu Ala Glu Pro Glu

2870 2875 2880

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

2885 2890 2895

Glu Thr Ala Ala Ala Ile Asn Ile Thr Ile Leu Glu Asp Asp Val

2900 2905 2910

Pro Glu Leu Glu Glu Tyr Phe Leu Val Asn Leu Thr Tyr Val Gly

2915 2920 2925

Leu Thr Met Ala Ala Ser Thr Ser Phe Pro Pro Arg Leu Asp Ser

2930 2935 2940

Glu Gly Leu Thr Ala Gln Val Ile Ile Asp Ala Asn Asp Gly Ala

2945 2950 2955

Arg Gly Val Ile Glu Trp Gln Gln Ser Arg Phe Glu Val Asn Glu

2960 2965 2970

Thr His Gly Ser Leu Thr Leu Val Ala Gln Arg Ser Arg Glu Pro

2975 2980 2985

Leu Gly His Val Ser Leu Phe Val Tyr Ala Gln Asn Leu Glu Ala

2990 2995 3000

Gln Val Gly Leu Asp Tyr Ile Phe Thr Pro Met Ile Leu His Phe

3005 3010 3015

Ala Asp Gly Glu Arg Tyr Lys Asn Val Asn Ile Met Ile Leu Asp

3020 3025 3030

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

3035 3040 3045

Asn Pro Ser Pro Gly Leu Glu Leu Gly Lys Asn Thr Ile Ala Leu

3050 3055 3060

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

3065 3070 3075

Asn Asn Ser Glu His Phe Phe Leu Arg Glu Pro Thr Ala Leu Tyr

3080 3085 3090

Val Gln Glu Ser Val Ala Val Leu Tyr Ile Val Arg Glu Pro Ala

3095 3100 3105

Gln Gly Leu Phe Gly Thr Val Thr Val Gln Phe Ile Val Thr Glu

3110 3115 3120

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

3125 3130 3135

Tyr Ile Val Leu Glu Glu Gly Val Arg Phe Lys Ala Leu Gln Ile

3140 3145 3150

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

3155 3160 3165

Cys Thr Leu Phe Asn Pro Thr Gly Gly Ala Arg Leu Gly Val His

3170 3175 3180

Val Gln Thr Leu Ile Thr Val Leu Gln Asn Gln Ala Pro Leu Gly

3185 3190 3195

Leu Phe Ser Ile Ser Ala Val Glu Asn Arg Ala Thr Ser Ile Asp

3200 3205 3210

Ile Glu Glu Ala Asn Arg Thr Val Tyr Leu Asn Val Ser Arg Thr

3215 3220 3225

Asn Gly Ile Asp Leu Ala Val Ser Val Gln Trp Glu Thr Val Ser

3230 3235 3240

Glu Thr Ala Phe Gly Met Arg Gly Met Asp Val Val Phe Ser Val

3245 3250 3255

Phe Gln Ser Phe Leu Asp Glu Ser Ala Ser Gly Trp Cys Phe Phe

3260 3265 3270

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

3275 3280 3285

Val Thr Val Tyr Arg Trp Gln Gly Ile Phe Ile Pro Val Glu Asp

3290 3295 3300

Leu Asn Ile Glu Asn Pro Lys Thr Cys Glu Ala Phe Asn Ile Gly

3305 3310 3315

Phe Ser Pro Tyr Phe Val Ile Thr His Glu Glu Arg Asn Glu Glu

3320 3325 3330

Lys Pro Ser Leu Asn Ser Val Phe Thr Phe Thr Ser Gly Phe Lys

3335 3340 3345

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

3350 3355 3360

Arg Tyr Phe Thr Ser Asp Ser Gln Asp Tyr Leu Ile Ile Ala Ser

3365 3370 3375

Gln Arg Asp Asp Ser Glu Leu Thr Gln Val Phe Arg Trp Asn Gly

3380 3385 3390

Gly Ser Phe Val Leu His Gln Lys Leu Pro Val Arg Gly Val Leu

3395 3400 3405

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

3410 3415 3420

Ser Gln Ala Asn Ala Arg Leu Asn Ser Leu Leu Phe Arg Trp Ser

3425 3430 3435

Gly Ser Gly Phe Ile Asn Phe Gln Glu Val Pro Val Ser Gly Thr

3440 3445 3450

Thr Glu Val Glu Ala Leu Ser Ser Ala Asn Asp Ile Tyr Leu Ile

3455 3460 3465

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

3470 3475 3480

Phe Ile Trp Glu Met Gly Gln Ser Ser Phe Arg Tyr Phe Gln Ser

3485 3490 3495

Val Asp Phe Ala Ala Val Asn Arg Ile His Ser Phe Thr Pro Ala

3500 3505 3510

Ser Gly Ile Ala His Ile Leu Leu Ile Gly Gln Asp Met Ser Ala

3515 3520 3525

Leu Tyr Cys Trp Asn Ser Glu Arg Asn Gln Phe Ser Phe Val Leu

3530 3535 3540

Glu Val Pro Ser Ala Tyr Asp Val Ala Ser Val Thr Val Lys Ser

3545 3550 3555

Leu Asn Ser Ser Lys Asn Leu Ile Ala Leu Val Gly Ala His Ser

3560 3565 3570

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

3575 3580 3585

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

3590 3595 3600

Thr Ile Ala Val Asn Ile Leu Asp Asp Thr Val Pro Glu Lys Glu

3605 3610 3615

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

3620 3625 3630

Ile Gly Ile Asn Asp Ser Val Thr Ile Thr Ile Leu Ser Asn Asp

3635 3640 3645

Asp Ala Tyr Gly Ile Val Ala Phe Ala Gln Asn Ser Leu Tyr Lys

3650 3655 3660

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

3665 3670 3675

Glu Arg Leu Lys Gly Thr Tyr Gly Arg Ile Thr Ile Ala Trp Glu

3680 3685 3690

Ala Asp Gly Ser Ile Ser Asp Ile Phe Pro Thr Ser Gly Val Ile

3695 3700 3705

Leu Phe Thr Glu Gly Gln Val Leu Ser Thr Ile Thr Leu Thr Ile

3710 3715 3720

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

3725 3730 3735

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

3740 3745 3750

Ala Thr Ile Asp Gln Asp Arg Ser Lys Ser Val Ile Thr Thr Leu

3755 3760 3765

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

3770 3775 3780

Val Phe Ile Arg Val Ala Glu Pro Lys Glu Asn Thr Thr Thr Leu

3785 3790 3795

Gln Leu Gln Ile Ala Arg Asp Lys Gly Leu Leu Gly Asp Ile Ala

3800 3805 3810

Ile His Leu Arg Ala Gln Pro Asn Phe Leu Leu His Val Asp Asn

3815 3820 3825

Gln Ala Thr Glu Asn Glu Asp Tyr Val Leu Gln Glu Thr Ile Ile

3830 3835 3840

Ile Met Lys Glu Asn Ile Lys Glu Ala His Ala Glu Val Ser Ile

3845 3850 3855

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

3860 3865 3870

Ile Thr Glu Val Asn Leu Val Asn Ser Asp Phe Ser Thr Gly Gln

3875 3880 3885

Pro Ser Val Arg Arg Pro Gly Met Glu Ile Ala Glu Ile Met Ile

3890 3895 3900

Glu Glu Asn Asp Asp Pro Arg Gly Ile Phe Met Phe His Val Thr

3905 3910 3915

Arg Gly Ala Gly Glu Val Ile Thr Ala Tyr Glu Val Pro Pro Pro

3920 3925 3930

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

3935 3940 3945

Gly Ala Val Asn Val Tyr Trp Lys Ala Ser Pro Asp Ser Ala Gly

3950 3955 3960

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

3965 3970 3975

Lys Gln Val Thr Ala Met Ile Glu Ile Thr Ile Ile Asp Asp Ala

3980 3985 3990

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

3995 4000 4005

Ala Gly Gly Gly Arg Leu Gly Asp Asp Val Val Val Thr Val Val

4010 4015 4020

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

4025 4030 4035

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

4040 4045 4050

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

4055 4060 4065

Thr Val Arg Leu Glu Trp Thr Ile Asp Glu Lys Ala Lys His Asn

4070 4075 4080

Leu Ser Pro Leu Asn Gly Thr Leu His Phe Asp Glu Thr Glu Ser

4085 4090 4095

Gln Lys Thr Ile Val Leu His Thr Leu Gln Asp Thr Val Leu Glu

4100 4105 4110

Glu Asp Arg Arg Phe Thr Ile Gln Leu Ile Ser Ile Asp Glu Val

4115 4120 4125

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

4130 4135 4140

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

4145 4150 4155

His Ile Leu Ile Gly Glu Pro Ser Ala Lys Tyr Asn Gly Thr Ala

4160 4165 4170

Ile Ile Ser Leu Val Arg Gly Pro Gly Ile Leu Gly Glu Val Thr

4175 4180 4185

Val Phe Trp Arg Ile Phe Pro Pro Ser Val Gly Glu Phe Ala Glu

4190 4195 4200

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

4205 4210 4215

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

4220 4225 4230

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

4235 4240 4245

Ser Glu Ser Ser Ser Thr Ala Asn Ile Thr Val Val Ala Ser Asp

4250 4255 4260

Ser Pro Tyr Gly Arg Phe Ala Phe Ser His Glu Gln Leu Arg Val

4265 4270 4275

Ser Glu Ala Gln Arg Val Asn Ile Thr Ile Ile Arg Ser Ser Gly

4280 4285 4290

Asp Phe Gly His Val Arg Leu Trp Tyr Lys Thr Met Ser Gly Thr

4295 4300 4305

Ala Glu Ala Gly Leu Asp Phe Val Pro Ala Ala Gly Glu Leu Leu

4310 4315 4320

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

4325 4330 4335

Asp Asp Asp Tyr Pro Glu Gly Pro Glu Glu Phe Ser Leu Thr Ile

4340 4345 4350

Thr Lys Val Glu Leu Gln Gly Arg Gly Tyr Asp Phe Thr Ile Gln

4355 4360 4365

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

4370 4375 4380

Ser Ile Val Arg Ile Ile Ile Met Lys Asn Asp Asn Ala Glu Gly

4385 4390 4395

Ile Ile Glu Phe Asp Pro Lys Tyr Thr Ala Phe Glu Val Glu Glu

4400 4405 4410

Asp Val Gly Leu Ile Met Ile Pro Val Val Arg Leu His Gly Thr

4415 4420 4425

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

4430 4435 4440

Ser Pro Gly Gly Val Asp Tyr Ile Leu His Gly Ser Thr Val Thr

4445 4450 4455

Phe Gln His Gly Gln Asn Leu Ser Phe Ile Asn Ile Ser Ile Ile

4460 4465 4470

Asp Asp Asn Glu Ser Glu Phe Glu Glu Pro Ile Glu Ile Leu Leu

4475 4480 4485

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

4490 4495 4500

Arg Ile Ile Ile Ala Lys Ser Asp Ser Pro Phe Gly Val Ile Arg

4505 4510 4515

Phe Leu Asn Gln Ser Lys Ile Ser Ile Ala Asn Pro Asn Ser Thr

4520 4525 4530

Met Ile Leu Ser Leu Val Leu Glu Arg Thr Gly Gly Leu Leu Gly

4535 4540 4545

Glu Ile Gln Val Asn Trp Glu Thr Val Gly Pro Asn Ser Gln Glu

4550 4555 4560

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

4565 4570 4575

Leu Phe Tyr Phe Gly Glu Gly Glu Gly Gly Val Arg Thr Ile Ile

4580 4585 4590

Leu Thr Ile Tyr Pro His Glu Glu Ile Glu Val Glu Glu Thr Phe

4595 4600 4605

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

4610 4615 4620

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

4625 4630 4635

Asn Gly Val Val Gln Phe Ala Pro Glu Thr Leu Ser Lys Lys Thr

4640 4645 4650

Tyr Ser Glu Pro Leu Ala Leu Glu Gly Pro Leu Leu Ile Thr Phe

4655 4660 4665

Phe Val Arg Arg Val Lys Gly Thr Phe Gly Glu Ile Met Val Tyr

4670 4675 4680

Trp Glu Leu Ser Ser Glu Phe Asp Ile Thr Glu Asp Phe Leu Ser

4685 4690 4695

Thr Ser Gly Phe Phe Thr Ile Ala Asp Gly Glu Ser Glu Ala Ser

4700 4705 4710

Phe Asp Val His Leu Leu Pro Asp Glu Val Pro Glu Ile Glu Glu

4715 4720 4725

Asp Tyr Val Ile Gln Leu Val Ser Val Glu Gly Gly Ala Glu Leu

4730 4735 4740

Asp Leu Glu Lys Ser Ile Thr Trp Phe Ser Val Tyr Ala Asn Asp

4745 4750 4755

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

4760 4765 4770

Leu Ile Gly Gln Asn Leu Ile Arg Ser Ile Gln Ile Asn Ile Thr

4775 4780 4785

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

4790 4795 4800

Ser Ser Asp His Lys Glu Gln Pro Ile Val Thr Glu Asn Ala Glu

4805 4810 4815

Arg Gln Leu Val Val Lys Asp Gly Ala Thr Tyr Lys Val Asp Val

4820 4825 4830

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

4835 4840 4845

Thr Leu Gln Leu Val Thr Val Met Leu Val Gly Gly Arg Phe Tyr

4850 4855 4860

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

4865 4870 4875

Val Ser Glu Lys Ala Ala Asn Ser Gln Val Gly Phe Glu Ser Thr

4880 4885 4890

Ala Phe Gln Leu Met Asn Ile Thr Ala Gly Thr Ser His Val Met

4895 4900 4905

Ile Ser Arg Arg Gly Thr Tyr Gly Ala Leu Ser Val Ala Trp Thr

4910 4915 4920

Thr Gly Tyr Ala Pro Gly Leu Glu Ile Pro Glu Phe Ile Val Val

4925 4930 4935

Gly Asn Met Thr Pro Thr Leu Gly Ser Leu Ser Phe Ser His Gly

4940 4945 4950

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

4955 4960 4965

Trp Pro Glu Ala Phe Val Leu His Leu Ser Gly Val Gln Ser Ser

4970 4975 4980

Ala Pro Gly Gly Ala Gln Leu Arg Ser Gly Phe Ile Val Ala Glu

4985 4990 4995

Ile Glu Pro Met Gly Val Phe Gln Phe Ser Thr Ser Ser Arg Asn

5000 5005 5010

Ile Ile Val Ser Glu Asp Thr Gln Met Ile Arg Leu His Val Gln

5015 5020 5025

Arg Leu Phe Gly Phe His Ser Asp Leu Ile Lys Val Ser Tyr Gln

5030 5035 5040

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

5045 5050 5055

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

5060 5065 5070

Phe Glu Ile Thr Ile Ile Asn Asp Gln Leu Ser Glu Ile Glu Glu

5075 5080 5085

Phe Phe Tyr Ile Asn Leu Thr Ser Val Glu Ile Arg Gly Leu Gln

5090 5095 5100

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

5105 5110 5115

Val Ala Val Ile Thr Ile Leu Asp Asn Asp Asp Leu Ala Gly Met

5120 5125 5130

Asp Ile Ser Phe Pro Glu Thr Thr Val Ala Val Ala Val Asp Thr

5135 5140 5145

Thr Leu Ile Pro Val Glu Thr Glu Ser Thr Thr Tyr Leu Ser Thr

5150 5155 5160

Ser Lys Thr Thr Thr Ile Leu Gln Pro Thr Asn Val Val Ala Ile

5165 5170 5175

Val Thr Glu Ala Thr Gly Val Ser Ala Ile Pro Glu Lys Leu Val

5180 5185 5190

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

5195 5200 5205

Thr Val Thr Ala Asn Val Ser Ile His Gly Thr Phe Ser Leu Gly

5210 5215 5220

Pro Ser Ile Val Tyr Ile Glu Glu Glu Met Lys Asn Gly Thr Phe

5225 5230 5235

Asn Thr Ala Glu Val Leu Ile Arg Arg Thr Gly Gly Phe Thr Gly

5240 5245 5250

Asn Val Ser Ile Thr Val Lys Thr Phe Gly Glu Arg Cys Ala Gln

5255 5260 5265

Met Glu Pro Asn Ala Leu Pro Phe Arg Gly Ile Tyr Gly Ile Ser

5270 5275 5280

Asn Leu Thr Trp Ala Val Glu Glu Glu Asp Phe Glu Glu Gln Thr

5285 5290 5295

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

5300 5305 5310

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

5315 5320 5325

Tyr Val Phe Leu Thr Asn Pro Gln Gly Gly Ala Gln Ile Val Glu

5330 5335 5340

Glu Lys Asp Asp Thr Gly Phe Ala Ala Phe Ala Met Val Ile Ile

5345 5350 5355

Thr Gly Ser Asp Leu His Asn Gly Ile Ile Gly Phe Ser Glu Glu

5360 5365 5370

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

5375 5380 5385

Leu His Leu Ile Val Thr Arg Gln Pro Asn Arg Ala Phe Glu Asp

5390 5395 5400

Val Lys Val Phe Trp Arg Val Thr Leu Asn Lys Thr Val Val Val

5405 5410 5415

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

5420 5425 5430

Ser Gly Thr Thr Thr Cys Thr Met Gly Gln Thr Lys Cys Phe Ile

5435 5440 5445

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

5450 5455 5460

Phe Phe Val Glu Leu Tyr Glu Ala Thr Ala Gly Ala Ala Ile Asn

5465 5470 5475

Asn Ser Ala Arg Phe Ala Gln Ile Lys Ile Leu Glu Ser Asp Glu

5480 5485 5490

Ser Gln Ser Leu Val Tyr Phe Ser Val Gly Ser Arg Leu Ala Val

5495 5500 5505

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

5510 5515 5520

Ser Gly Thr Gly Leu Met Met Ser Val Asn Phe Ser Thr Gln Glu

5525 5530 5535

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

5540 5545 5550

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

5555 5560 5565

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

5570 5575 5580

Glu Thr Gly Ser Leu Asn Ser Phe Pro Lys Arg Phe Gln Ile Val

5585 5590 5595

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

5600 5605 5610

Thr Ala Asn Ile Thr Leu Val Ser Asp Ala Asp Ser Gln Ala Ile

5615 5620 5625

Trp Gly Leu Ala Asp Gln Leu His Gln Pro Val Asn Asp Asp Ile

5630 5635 5640

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

5645 5650 5655

Asn Thr Asp Glu Gln Leu Ser Ala Met Met His Leu Ile Glu Lys

5660 5665 5670

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

5675 5680 5685

Thr Leu Phe Tyr Glu Ile Leu Cys Ser Leu Ile Asn Pro Lys Arg

5690 5695 5700

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

5705 5710 5715

Phe Ala Phe Ser Leu Leu Thr Asn Val Thr Cys Gly Ser Pro Gly

5720 5725 5730

Glu Lys Ser Lys Thr Ile Leu Asp Ser Cys Pro Tyr Leu Ser Ile

5735 5740 5745

Leu Ala Leu His Trp Tyr Pro Gln Gln Ile Asn Gly His Lys Phe

5750 5755 5760

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

5765 5770 5775

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

5780 5785 5790

Leu Val Gln Phe Thr Glu Tyr Ser Ser Gln Gln Trp Phe Ile Ser

5795 5800 5805

Gly Asn Asn Leu Pro Thr Leu Lys Asn Lys Val Leu Ser Leu Ser

5810 5815 5820

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

5825 5830 5835

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

5840 5845 5850

Ser Leu Cys Leu Leu Trp Asn Gln Ala Ala Ala Ser Trp Leu Ser

5855 5860 5865

Asp Ser Gln Phe Cys Lys Val Val Glu Glu Thr Ala Asp Tyr Val

5870 5875 5880

Glu Cys Ala Cys Ser His Met Ser Val Tyr Ala Val Tyr Ala Arg

5885 5890 5895

Thr Asp Asn Leu Ser Ser Tyr Asn Glu Ala Phe Phe Thr Ser Gly

5900 5905 5910

Phe Ile Cys Ile Ser Gly Leu Cys Leu Ala Val Leu Ser His Ile

5915 5920 5925

Phe Cys Ala Arg Tyr Ser Met Phe Ala Ala Lys Leu Leu Thr His

5930 5935 5940

Met Met Ala Ala Ser Leu Gly Thr Gln Ile Leu Phe Leu Ala Ser

5945 5950 5955

Ala Tyr Ala Ser Pro Gln Leu Ala Glu Glu Ser Cys Ser Ala Met

5960 5965 5970

Ala Ala Val Thr His Tyr Leu Tyr Leu Cys Gln Phe Ser Trp Met

5975 5980 5985

Leu Ile Gln Ser Val Asn Phe Trp Tyr Val Leu Val Met Asn Asp

5990 5995 6000

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

6005 6010 6015

Gly Leu Pro Ala Phe Val Val Ile Leu Leu Ile Val Ile Leu Lys

6020 6025 6030

Gly Ile Tyr His Gln Ser Met Ser Gln Ile Tyr Gly Leu Ile His

6035 6040 6045

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

6050 6055 6060

Ala Ala Leu Val Pro Leu Thr Cys Leu Val Val Val Phe Val Val

6065 6070 6075

Phe Ile His Ala Tyr Gln Val Lys Pro Gln Trp Lys Ala Tyr Asp

6080 6085 6090

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

6095 6100 6105

Leu Tyr Leu Phe Ala Leu Ile Ser Val Thr Trp Leu Trp Gly Gly

6110 6115 6120

Leu His Met Ala Tyr Arg His Phe Trp Met Leu Val Leu Phe Val

6125 6130 6135

Ile Phe Asn Ser Leu Gln Gly Leu Tyr Val Phe Met Val Tyr Phe

6140 6145 6150

Ile Leu His Asn Gln Met Cys Cys Pro Met Lys Ala Ser Tyr Thr

6155 6160 6165

Val Glu Met Asn Gly His Pro Gly Pro Ser Thr Ala Phe Phe Thr

6170 6175 6180

Pro Gly Ser Gly Met Pro Pro Ala Gly Gly Glu Ile Ser Lys Ser

6185 6190 6195

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

6200 6205 6210

Glu Arg Ala Ser Phe Gln Gln Gly Ser Gln Ala Ser Pro Asp Leu

6215 6220 6225

Lys Pro Ser Pro Gln Asn Gly Ala Thr Phe Pro Ser Ser Gly Gly

6230 6235 6240

Tyr Gly Gln Gly Ser Leu Ile Ala Asp Glu Glu Ser Gln Glu Phe

6245 6250 6255

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

6260 6265 6270

Ser Asp Asn Glu Ser Gly Gln Gly Ser Gln Glu Gly Gly Thr Leu

6275 6280 6285

Thr Asp Ser Gln Ile Val Glu Leu Arg Arg Ile Pro Ile Ala Asp

6290 6295 6300

Thr His Leu

6305

Claims (2)

1.检测生物标志物的引物或探针在制备癫痫辅助诊断试剂盒、癫痫产前诊断试剂盒或新生儿癫痫筛查试剂盒中的应用，其特征在于，所述生物标志物其相对于正常GPR98基因的编码序列具有突变c.A6812G，所述正常GPR98基因的转录本编号为NM_032119.3，所述生物标志物的碱基序列如SEQ ID NO.1所示。

2.根据权利要求1所述的应用，其特征在于，所述探针相对于正常GPR98基因的编码序列的第6812位的碱基为G。

Images