CN102558312B - 一种慢性乙型病毒性肝炎相关基因nlrx1的新突变蛋白、编码基因及其应用 - Google Patents
一种慢性乙型病毒性肝炎相关基因nlrx1的新突变蛋白、编码基因及其应用 Download PDFInfo
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Abstract
本发明公开了一种慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白、编码基因及其应用。本发明的慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白是在慢性乙型病毒性肝炎相关基因NLRX1蛋白的氨基酸序列第707位精氨酸突变为半胱氨酸，同时得到了该突变蛋白的编码基因，建立了基于NLRX1基因及其突变体的诊断试剂盒，该试剂盒可以对临床上慢性乙肝患者进行基因水平的诊断，还可以对其临床用药情况予以指导和个体化治疗。从长远看，对慢性乙型病毒性肝炎进行NLRX1基因的突变检测使我们有可能在今后通过纠正突变的基因疗法或其它针对这一突变的生物学效应的方法去治疗本病，在临床治疗方面有深远意义和应用前景。
Description
技术领域
本发明涉及生物工程及医学技术领域，具体涉及一种慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白、编码基因及其应用。
背景技术
慢性乙型病毒性肝炎（慢性乙肝）是由乙型肝炎病毒（HBV）感染而引起的以肝脏损害为主要表现的传染性疾病，是关系到我国乃至全球公共卫生的重大疾病。宿主的遗传背景在其易感性及免疫应答中起重要作用。而人群对乙肝免疫力的高低存在明显的个体差异。
中国专利200810004159.5公开了一种与肝细胞癌相关的乙型肝炎病毒基因组标志物以及预测HBV感染个体发展成肝细胞癌(HCC)的遗传素因的试剂盒。该试剂盒包括一种或更多种探针，当其与HBV基因组接触时，如果所述基因组为NLRX1基因型、且包括至少一种对应于某段核苷酸序列上的核苷酸（170C;和/或2170G2;和/或2441C;和/或799G）时会选择性地与所述基因组杂交。
发明内容
本发明的目的在于提供一种慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白。
本发明的另一目的是提供上述慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白的编码基因。
本发明的又一目的是提供上述慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白、该突变蛋白的编码基因的应用。
本发明通过以下技术方案实现上述目的：
一种慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白，是在慢性乙型病毒性肝炎相关基因NLRX1蛋白的氨基酸序列第707位精氨酸Arg突变为半胱氨酸Cys，本发明中用p.Arg707Cys表示。
上述慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白，氨基酸序列如SEQ ID NO:1所示。
上述慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白的编码基因。该编码基因的核苷酸序列优选如SEQ ID NO:2所示。
慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白在制备慢性乙型病毒性肝炎的检测试剂中的应用。
慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白的编码基因在制备慢性乙型病毒性肝炎的检测试剂中的应用。
一种慢性乙型病毒性肝炎检测试剂盒，由以下成分组成：核苷酸序列如SEQ ID NO:3和SEQ ID NO:4所示的引物，PCR反应液，PCR产物纯化盒和测序反应液；
所述PCR反应液为溶解了Tag DNA聚合酶、dNTPs、镁离子（如MgCl2）、PCR反应缓冲液（如10×Taq Buffer），以上试剂均可直接购买相应商品，如（10mM）dNTPs购自上海生工生物工程技术服务有限公司；Tag DNA聚合酶及其配套的10×Taq Buffer、MgCl2购自Fermentas公司。各试剂的用量及浓度均为本领域常规值，如1u/μL Tag DNA聚合酶1μL、2mmol/L 的dNTP（即浓度均为2mmol/L 的4种dNTP的混合物）3μL、25mmol/L MgCl2 3μL、10×Taq Buffer（内含(NH4)2SO4）3μL、灭菌ddH2O 17μL。
所述PCR产物纯化盒为纯化PCR产物的溶液和DNA吸附柱Labell；所述纯化PCR产物的溶液为：1u/μL虾碱性磷酸酶（SAP，可购于Fermentas公司）0.6μL、20u/μL外切酶（Exo I，可购于Fermentas公司）0.15μL和灭菌ddH2O 1.25-1.75μL，或按上述比例配制的其他体积的混合液。纯化PCR产物的溶液优选2-2.5μL。
所述测序反应液为BigDye（购自ABI公司）和5×Sequence buffer（购自ABI公司）的混合液，BigDye和5×Sequence buffer的体积比优选为1:2，如1μLBigDye与2μL5×Sequence buffer混合。
上述慢性乙型病毒性肝炎检测试剂盒，优选核苷酸序列如SEQ ID NO:3和SEQ ID NO:4所示的引物浓度分别为3.2μmol/L。
本发明的慢性乙型病毒性肝炎的相关基因NLRX1及其新突变p.Arg707Cys，是通过对“相对极端性状的”50例慢性乙肝患者及40例未注射过乙肝疫苗正常对照进行全基因组外显子测序，通过生物信息学分析及进一步的数据筛选找到最有可能的候选基因；然后再对所找到的候选基因进行大样本量的病例-对照（其中慢性乙肝患者1728例，未注射乙肝疫苗正常对照1636例）相关关系研究；最后通过相关基因的作用机理及统计学分析结果（NLRX1基因新突变与慢性乙肝相关的统计学P 值为5.08×10-5，优势比（OR）为2.34，说明两者有显著相关性）最终确定了NLRX1基因新突变与慢性乙型肝炎相关。
本发明的人NLRX1基因核苷酸全长序列（包含突变位点）通常是用聚合酶链式反应（PCR）进行合成。对于PCR扩增法，可根据NLRX1基因的核苷酸序列，进行引物设计，并以所检测的患慢性乙型肝炎患者抽提的DNA作为模板，扩增目的序列。最后通过测序反应检测及确定相关基因的突变。
由于前期的研究已经证明了慢性乙型肝炎与NLRX1基因新突变的高度相关性，因此检测这个基因的突变可用于鉴定慢性乙型肝炎患者的宿主遗传背景的易感性及对免疫应答的反应能力，进一步地用于之后靶向个体化治疗。
与现有技术相比，本发明具有以下有益效果：
我们通过全基因组外显子测序及大样本量的相关研究，发现了与慢性乙型病毒性肝炎的相关基因——NLRX1及其新突变。因此，找寻及检测慢性乙肝相关基因及其突变，不仅是了解及阐明本病的发病机理的必要途径，同时也为建立鉴定本病的基因诊断和个体化治疗提供了新的契机。在已了解与本病相关的NLRX1基因及其突变之后，我们可以建立起基于NLRX1基因及其变异的诊断技术，以期对临床上慢性乙肝患者进行基因水平的诊断，还可以对其临床用药情况予以指导和个体化治疗。由于基因的突变是导致本病遗传背景发生改变从而致使其易感性及免疫应答发生改变的重要因素，从长远看，对本病进行NLRX1基因的突变检测使我们有可能在今后通过纠正突变的基因疗法或其它针对这一突变的生物学效应的方法去治疗本病。因此，从长远看，与本病相关的NLRX1基因突变的发现在临床治疗方面有深远的意义和前景。
附图说明
图1：NLRX1基因的部分测序结果，图中上部为NLRX1野生型的测序结果，图下部为NLRX1 p.Arg707Cys杂合性突变的测序结果（箭头所示为突变位点）。
具体实施方式
以下实施例中如无特殊说明均为本领域常规试剂和试验方法。
实施例1 病例收集
来自中山大学附属第三医院传染科的1728例慢性乙型肝炎患者和来自同一地区的1636例未注射乙肝疫苗或自报疫苗注射史不明的健康自愿者，在取得上述患者、自愿者及家属知情同意后，取外周血于EDTA抗凝管中备用。用Qiagen公司生产的QIAamp DNA Blood Mini Kits（试剂盒）从抗凝外周血中提取DNA，TE溶解，-80℃保存，备用。
实施例2 NLRX1基因的突变检测
NLRX1基因的mRNA序列来自Genbank（NM_170722）。Genomic DNA序列来自UCSC数据库（http://genome.ucsc.edu/）和Ensembl数据库（http://asia.ensembl.org/index.html）。
主要步骤：
1. PCR扩增：PCR反应体积为30μL：10×Taq Buffer（内含(NH4)2SO4）3μL，25mmol/L MgCl2 3μL，2mmol/L dNTP混合物3μL，3.2μmol/L上、下游引物各1μL，1u/μL Taq DNA聚合酶1μL，实施例1提取的DNA模板1μL，灭菌ddH2O补足体积至30μL。PCR反应条件：95℃预变性3min；95℃ 30s，引物特异性退火温度1min，72℃ 45s，36个循环；最后72℃ 延伸10min。
检测NLRX1基因突变位点的上游引物P1（SEQ ID NO：3）的序列为：5’- CCCCATCAGAGCTCCTTGACC-3’，下游引物P2（SEQ ID NO：4）的序列为：5’- CTCCCGGCCCCTAAACTAGACT-3’。
2. 测序反应方案
（1）预反应：反应体积共3μL：1u/μL虾碱性磷酸酶（SAP）0.6μL、20u/μL外切酶（Exo I）0.15μL （Fermentas公司）、PCR产物0.5-1.0μL、灭菌ddH2O补足体积至3μL。反应混合物在PCR仪上反应，37℃温浴15min，85℃ 15min灭活酶。反应完毕后反应混合物直接作为测序反应的模板用。
（2）测序反应：用ABI公司的96孔板，在GeneAmp 9700 PCR仪上进行。反应体积共10μL：3μL的预反应产物、2μL的5×Sequence buffer（ABI公司）、1μL的Big-Dye（ABI公司）、1μL的引物（3.2μmol/L），3μL的灭菌ddH2O。反应条件：98℃ 2min；96℃ 10s，50℃ 5s，60℃ 4min，30个循环；最后4℃保存。
（3）测序纯化：直接在96孔板上进行。
a) 测序反应完毕后，配无水乙醇6mL+3mol/L醋酸钠（pH5.2）240μL混合溶液（即无水乙醇：醋酸钠体积比=25:1），每个样品中加入50μL混合溶液。用锡箔纸封闭，并振荡混匀。
b) 将测序产物放于-20℃避光静置20min以上。
c) 20℃，3700 rpm离心30min。
d) 倒去上清液，倒扣在四层吸水纸上，360rpm离心10s。
e) 配75%乙醇（无水乙醇7.5mL+ddH2O 2.5mL混合溶液的比例），每个样品中加入90μL混合溶液。用锡箔纸封闭，并振荡混匀。
f) 将测序产物放于-20℃避光静置20min以上。
g) 20℃，3700 rpm离心30min。
h) 倒去上清液，倒扣在四层吸水纸上，360rpm离心10s。
i) 室温通风处，避光晾干，30min以上。
j) 每个样品中加ddH2O 10μL，用锡箔纸封闭，振荡后离心。
k) 待测样品放于4℃避光静置1.5h以上，以充分溶解，上ABI3730测序仪进行测序。
3. 测序结果分析：用ABI序列分析软件进行分析
发明人对来自中山大学附属第三医院传染科的1728例慢性乙型肝炎患者和来自同一地区的1636例未注射乙肝疫苗或自报疫苗注射史不明的健康自愿者进行NLRX1基因的突变检测。结果如下：
突变位点为：发生在NLRX1基因的氨基酸序列中第707位精氨酸突变为半胱氨酸（p.Arg707Cys），突变后的氨基酸序列如SEQ ID NO：1所示。其中有66例患者和30例正常对照存在杂合性突变。在1728例病例和1636例对照研究中，其风险等位基因的个数分别是66个和30个，优势比值（OR值）为2.34，P值为5.08×10-5。多基因遗传病的研究中，通常是通过关联分析来确定其风险基因的，本实验结果中，P值有显著差异，且OR值为2.34，说明该基因的突变是导致该病的危险因素。测序结果见图1。
实施例3NLRX1基因突变检测试剂盒的制备
制备—试剂盒，具体成分见表1
表1
| 试剂名称 | 具体成分 |
| 上游引物P1 | （SEQ ID NO：3），干粉 2 OD，溶解后浓度：3.2μmol/L，体积：1μL |
| 下游引物P2 | （SEQ ID NO：4），干粉 2 OD，溶解后浓度：3.2μmol/L，体积：1μL |
| PCR反应液 | 1u/μL Taq DNA聚合酶1μL（购自Fermentas公司）、2mmol/L dNTP 3μL、25mmol/LMgCl2 3μL（Taq DNA聚合酶配套试剂）、10×Taq Buffer（内含(NH4)2SO4，Taq DNA聚合酶配套试剂）3μL 、灭菌ddH2O 17μL。 |
| PCR产物纯化盒 | 2-2.5μL 纯化PCR产物的溶液（内含1u/μL虾碱性磷酸酶（SAP，购自Fermentas公司）0.6μL、20u/μL外切酶（Exo I，购自Fermentas公司）0.15μL和灭菌ddH2O 1.25-1.75μL），DNA吸附柱Labell |
| 测序反应液 | 含1μL BigDye和2μL 的5×Sequence buffer（均购自ABI公司） |
上述试剂盒的使用方法：抽取待检测患者的血液2mL，使用常规方法（或特定的DNA提取试剂盒）从血液中提取DNA。将NLRX1基因突变检测试剂盒中的PCR引物稀释至3.2μmol/L，以所提取的DNA为模板与所提供的引物进行PCR反应。使用检测试剂和所提供的PCR产物纯化盒对PCR产物进行纯化。将纯化的产物进行测序反应后直接测序。观察测序所得到的序列是否存在错义突变，即SEQ ID NO：1所示氨基酸序列第707位精氨酸（Arg）是否发生突变。
SEQUENCE LISTING
<110> 中山大学
<120> 一种慢性乙型病毒性肝炎相关基因NLRX1的新突变蛋白、编码基因及其应用
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Met Arg Trp Gly His His Leu Pro Arg Ala Ser Trp Gly Ser Gly Phe
1 5 10 15
Arg Arg Ala Leu Gln Arg Pro Asp Asp Arg Ile Pro Phe Leu Ile His
20 25 30
Trp Ser Trp Pro Leu Gln Gly Glu Arg Pro Phe Gly Pro Pro Arg Ala
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Phe Ile Arg His His Gly Ser Ser Val Asp Ser Ala Pro Pro Pro Gly
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Arg His Gly Arg Leu Phe Pro Ser Ala Ser Ala Thr Glu Ala Ile Gln
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Arg His Arg Arg Asn Leu Ala Glu Trp Phe Ser Arg Leu Pro Arg Glu
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Glu Arg Gln Phe Gly Pro Thr Phe Ala Leu Asp Thr Val His Val Asp
100 105 110
Pro Val Ile Arg Glu Ser Thr Pro Asp Glu Leu Leu Arg Pro Pro Ala
115 120 125
Glu Leu Ala Leu Glu His Gln Pro Pro Gln Ala Gly Leu Pro Pro Leu
130 135 140
Ala Leu Ser Gln Leu Phe Asn Pro Asp Ala Cys Gly Arg Arg Val Gln
145 150 155 160
Thr Val Val Leu Tyr Gly Thr Val Gly Thr Gly Lys Ser Thr Leu Val
165 170 175
Arg Lys Met Val Leu Asp Trp Cys Tyr Gly Arg Leu Pro Ala Phe Glu
180 185 190
Leu Leu Ile Pro Phe Ser Cys Glu Asp Leu Ser Ser Leu Gly Pro Ala
195 200 205
Pro Ala Ser Leu Cys Gln Leu Val Ala Gln Arg Tyr Thr Pro Leu Lys
210 215 220
Glu Val Leu Pro Leu Met Ala Ala Ala Gly Ser His Leu Leu Phe Val
225 230 235 240
Leu His Gly Leu Glu His Leu Asn Leu Asp Phe Arg Leu Ala Gly Thr
245 250 255
Gly Leu Cys Ser Asp Pro Glu Glu Pro Gln Glu Pro Ala Ala Ile Ile
260 265 270
Val Asn Leu Leu Arg Lys Tyr Met Leu Pro Gln Ala Ser Ile Leu Val
275 280 285
Thr Thr Arg Pro Ser Ala Ile Gly Arg Ile Pro Ser Lys Tyr Val Gly
290 295 300
Arg Tyr Gly Glu Ile Cys Gly Phe Ser Asp Thr Asn Leu Gln Lys Leu
305 310 315 320
Tyr Phe Gln Leu Arg Leu Asn Gln Pro Tyr Cys Gly Tyr Ala Val Gly
325 330 335
Gly Ser Gly Val Ser Ala Thr Pro Ala Gln Arg Asp His Leu Val Gln
340 345 350
Met Leu Ser Arg Asn Leu Glu Gly His His Gln Ile Ala Ala Ala Cys
355 360 365
Phe Leu Pro Ser Tyr Cys Trp Leu Val Cys Ala Thr Leu His Phe Leu
370 375 380
His Ala Pro Thr Pro Ala Gly Gln Thr Leu Thr Ser Ile Tyr Thr Ser
385 390 395 400
Phe Leu Arg Leu Asn Phe Ser Gly Glu Thr Leu Asp Ser Thr Asp Pro
405 410 415
Ser Asn Leu Ser Leu Met Ala Tyr Ala Ala Arg Thr Met Gly Lys Leu
420 425 430
Ala Tyr Glu Gly Val Ser Ser Arg Lys Thr Tyr Phe Ser Glu Glu Asp
435 440 445
Val Cys Gly Cys Leu Glu Ala Gly Ile Arg Thr Glu Glu Glu Phe Gln
450 455 460
Leu Leu His Ile Phe Arg Arg Asp Ala Leu Arg Phe Phe Leu Ala Pro
465 470 475 480
Cys Val Glu Pro Gly Arg Ala Gly Thr Phe Val Phe Thr Val Pro Ala
485 490 495
Met Gln Glu Tyr Leu Ala Ala Leu Tyr Ile Val Leu Gly Leu Arg Lys
500 505 510
Thr Thr Leu Gln Lys Val Gly Lys Glu Val Ala Glu Leu Val Gly Arg
515 520 525
Val Gly Glu Asp Val Ser Leu Val Leu Gly Ile Met Ala Lys Leu Leu
530 535 540
Pro Leu Arg Ala Leu Pro Leu Leu Phe Asn Leu Ile Lys Val Val Pro
545 550 555 560
Arg Val Phe Gly Arg Met Val Gly Lys Ser Arg Glu Ala Val Ala Gln
565 570 575
Ala Met Val Leu Glu Met Phe Arg Glu Glu Asp Tyr Tyr Asn Asp Asp
580 585 590
Val Leu Asp Gln Met Gly Ala Ser Ile Leu Gly Val Glu Gly Pro Arg
595 600 605
Arg His Pro Asp Glu Pro Pro Glu Asp Glu Val Phe Glu Leu Phe Pro
610 615 620
Met Phe Met Gly Gly Leu Leu Ser Ala His Asn Arg Ala Val Leu Ala
625 630 635 640
Gln Leu Gly Cys Pro Ile Lys Asn Leu Asp Ala Leu Glu Asn Ala Gln
645 650 655
Ala Ile Lys Lys Lys Leu Gly Lys Leu Gly Arg Gln Val Leu Pro Pro
660 665 670
Ser Glu Leu Leu Asp His Leu Phe Phe His Tyr Glu Phe Gln Asn Gln
675 680 685
Arg Phe Ser Ala Glu Val Leu Ser Ser Leu Arg Gln Leu Asn Leu Ala
690 695 700
Gly Val Cys Met Thr Pro Val Lys Cys Thr Val Val Ala Ala Val Leu
705 710 715 720
Gly Ser Gly Arg His Ala Leu Asp Glu Val Asn Leu Ala Ser Cys Gln
725 730 735
Leu Asp Pro Ala Gly Leu Arg Thr Leu Leu Pro Val Phe Leu Arg Ala
740 745 750
Arg Lys Leu Gly Leu Gln Leu Asn Ser Leu Gly Pro Glu Ala Cys Lys
755 760 765
Asp Leu Arg Asp Leu Leu Leu His Asp Gln Cys Gln Ile Thr Thr Leu
770 775 780
Arg Leu Ser Asn Asn Pro Leu Thr Ala Ala Gly Val Ala Val Leu Met
785 790 795 800
Glu Gly Leu Ala Gly Asn Thr Ser Val Thr His Leu Ser Leu Leu His
805 810 815
Thr Gly Leu Gly Asp Glu Gly Leu Glu Leu Leu Ala Ala Gln Leu Asp
820 825 830
Arg Asn Arg Gln Leu Gln Glu Leu Asn Val Ala Tyr Asn Gly Ala Gly
835 840 845
Asp Thr Ala Ala Leu Ala Leu Ala Arg Ala Ala Arg Glu His Pro Ser
850 855 860
Leu Glu Leu Leu Gln Gly Val Ala Ile Gln Met Cys Trp Lys Leu Pro
865 870 875 880
Leu Leu Pro Tyr Ala His Leu Trp Thr Pro Arg Met Pro Ser His Trp
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Cys Phe Leu Leu Ile Leu Met Pro Pro Leu Pro Gln Trp Tyr Asp Gly
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Leu Val Ala Pro Arg Gly Arg Cys Thr
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atgaggtggg gccaccattt gcccagggcc tcttggggct ctggttttag aagagcactc 60
cagcgaccag atgatcgtat ccccttcctg atccactgga gttggcccct tcaaggggag 120
cgtccctttg ggccccctag ggcctttata cgccaccacg gaagctcggt agatagcgct 180
cccccacccg ggaggcatgg acggctgttc cccagcgcct ctgcaactga agctatacag 240
cggcaccgcc ggaacctggc tgagtggttc agccggctgc ccagggagga gcgccagttt 300
ggcccaacct ttgccctaga cacggtccac gttgaccctg tgatccgcga gagtacccct 360
gatgagctac ttcgcccacc cgcggagctg gccctggagc atcagccacc ccaggccggg 420
ctccccccac tggccttgtc tcagctcttt aacccggatg cctgtgggcg ccgggtgcag 480
acagtggtgc tgtatgggac agtgggcaca ggcaagagca cgctggtgcg caagatggtt 540
ctggactggt gttatgggcg gctgccggcc ttcgagctgc tcatcccctt ctcctgtgag 600
gacctgtcat ccctgggccc tgccccagcc tccctgtgcc aacttgtggc ccagcgctac 660
acgcccctga aggaggttct gcccctgatg gctgctgctg ggtcccacct cctctttgtg 720
ctccatggct tagagcatct caacctcgac ttccggctgg caggcacggg actttgtagt 780
gacccggagg aaccgcagga accagctgct atcatcgtca acctgctgcg caaatacatg 840
ctgcctcagg ccagcattct ggtgaccact cggccctctg ccattggccg tatccccagc 900
aagtacgtgg gccgctatgg tgagatctgc ggtttctctg ataccaacct gcagaagctc 960
tacttccagc tccgcctcaa ccagccgtac tgcgggtatg ccgttggcgg ttcaggtgtc 1020
tctgccacac cagctcagcg tgaccacctg gtgcagatgc tctcccggaa cctggagggg 1080
caccaccaga tagccgctgc ctgcttcctg ccgtcctatt gctggctcgt ttgtgccacc 1140
ttgcacttcc tgcatgcccc cacgcctgct gggcagaccc ttacaagcat ctataccagc 1200
ttcctgcgcc tcaacttcag cggggaaacc ctggacagca ctgacccctc caatttgtcc 1260
ctgatggcct atgcagcccg aaccatgggc aagttggcct atgagggggt gtcctcccgc 1320
aagacctact tctctgaaga ggatgtctgt ggctgcctgg aggctggcat caggacggag 1380
gaggagtttc agctgctgca catcttccgt cgggatgccc tgaggttttt cctggcccca 1440
tgtgtggagc cagggcgtgc aggcaccttc gtgttcaccg tgcccgccat gcaggaatac 1500
ctggctgccc tctacattgt gctgggtttg cgcaagacga ccctgcaaaa ggtgggcaag 1560
gaagtggctg agctcgtggg ccgtgttggg gaggacgtca gcctggtact gggcatcatg 1620
gccaagctgc tgcctctgcg ggctctgcct ctgctcttca acctgatcaa ggtggttcca 1680
cgagtgtttg ggcgcatggt gggtaaaagc cgggaggcgg tggctcaggc catggtgctg 1740
gagatgtttc gagaggagga ctactacaac gatgatgttc tggaccagat gggcgccagt 1800
atcctgggcg tggagggccc ccggcgccac ccagatgagc cccctgagga tgaagtcttc 1860
gagctcttcc ccatgttcat gggggggctt ctctctgccc acaaccgagc tgtgctagct 1920
cagcttggct gccccatcaa gaacctggat gccctggaga atgcccaggc catcaagaag 1980
aagctgggca agctgggccg gcaggtgctg cccccatcag agctccttga ccacctcttc 2040
ttccactatg agttccagaa ccagcgcttc tccgctgagg tgctcagctc cctgcgtcag 2100
ctcaacctgg caggtgtgtg catgacacca gtcaagtgca cagtggtggc agctgtgctg 2160
ggcagcggaa ggcatgccct ggatgaggtg aacttggcct cctgccagct agatcctgct 2220
gggctgcgca cactcctgcc tgtcttcctg cgtgcccgga agctgggctt gcaactcaac 2280
agcctgggcc ctgaggcctg caaggacctc cgagacctgt tgctgcatga ccagtgccaa 2340
attaccacac tgcggctgtc caacaacccg ctgacggcgg caggtgttgc cgtgctaatg 2400
gaggggctgg caggaaacac ctcagtgacg cacctgtccc tgctgcacac gggccttggg 2460
gacgaaggcc tggagctgct ggctgcccag ctggaccgca accggcagct gcaggagctg 2520
aacgtggcgt acaacggtgc tggtgacaca gcggccctgg ccctggccag agctgcccgg 2580
gagcaccctt ccctggaact gctacagggt gtcgccatcc agatgtgttg gaagcttccc 2640
ctcctgcctt atgctcacct gtggacaccg aggatgccct cacattggtg ctttctcctc 2700
atcctcatgc cccctttgcc acaatggtat gatggcttgg tagcccctcg aggcagatgc 2760
acctga 2766
<210> 3
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<213> 人工序列
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ccccatcaga gctccttgac c 21
<210> 4
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<212> DNA
<213> 人工序列
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ctcccggccc ctaaactaga ct 22
Claims (6)
1.一种慢性乙型病毒性肝炎相关基因NLRX1的突变蛋白，其特征在于在慢性乙型病毒性肝炎相关基因NLRX1蛋白的氨基酸序列第707位精氨酸突变为半胱氨酸；所述NLRX1的突变蛋白的氨基酸序列如SEQ ID NO:1所示。
2.权利要求1所述慢性乙型病毒性肝炎相关基因NLRX1的突变蛋白的编码基因；所述NLRX1的突变蛋白的编码基因的核苷酸序列如SEQ ID NO:2所示。
3.权利要求1所述慢性乙型病毒性肝炎相关基因NLRX1的突变蛋白在制备慢性乙型病毒性肝炎的检测试剂中的应用。
4.权利要求2所述慢性乙型病毒性肝炎相关基因NLRX1的突变蛋白的编码基因在制备慢性乙型病毒性肝炎的检测试剂中的应用。
5.一种慢性乙型病毒性肝炎检测试剂盒，其特征在于由以下成分组成：核苷酸序列如SEQ ID NO:3和SEQ ID NO:4所示的引物，PCR反应液，PCR产物纯化盒和测序反应液；
所述PCR反应液为溶解了Tag DNA聚合酶、dNTPs、镁离子和PCR反应缓冲液，PCR反应缓冲液内含(NH4)2SO4；
所述PCR产物纯化盒由纯化PCR产物的溶液和DNA吸附柱Labell组成，所述纯化PCR产物的溶液为1u/μL虾碱性磷酸酶、20u/μL外切酶ExoI和灭菌ddH2O的混合液；
所述测序反应液为BigDye和5×Sequence buffer的混合液。
6.根据权利要求5所述慢性乙型病毒性肝炎检测试剂盒，其特征在于所述核苷酸序列如SEQ ID NO:3和SEQ ID NO:4所示的引物浓度分别为3.2μmol/L。
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| US7923545B2 (en) * | 2002-04-30 | 2011-04-12 | The University Of North Carolina At Chapel Hill | Caterpiller gene family |
| CN102178927A (zh) * | 2011-03-01 | 2011-09-14 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 干扰素诱导跨膜蛋白3在制备抗乙型肝炎病毒感染药物中的用途 |
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| CN101255474A (zh) * | 2004-09-10 | 2008-09-03 | 香港中文大学 | 与肝细胞癌相关的乙型肝炎病毒基因组标志物 |
| CN102178927A (zh) * | 2011-03-01 | 2011-09-14 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 干扰素诱导跨膜蛋白3在制备抗乙型肝炎病毒感染药物中的用途 |
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