CN108265060B - 远端关节弯曲病的致病基因及其用途 - Google Patents
远端关节弯曲病的致病基因及其用途 Download PDFInfo
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Abstract
本发明鉴定了远端关节弯曲病的相关的致病基因—MET致病基因。在此基础上,本发明提供了突变的MET基因及其用途,包含突变的MET基因的载体、宿主细胞以及试剂盒。此外,本发明还提供了用于诊断远端关节弯曲病的方法,用于所述方法的诊断剂,以及包含所述诊断剂的试剂盒。
Description
技术领域
本发明涉及分子遗传学领域以及疾病的诊断和治疗领域。特别地,本发明鉴定了与远端关节弯曲病相关的致病基因—MET基因。在此基础上,本发明提供了突变的MET基因及其用途,包含突变的MET基因的载体、宿主细胞以及试剂盒。此外,本发明还提供了用于诊断远端关节弯曲病的方法,用于所述方法的诊断剂,以及包含所述诊断剂的试剂盒。
背景技术
远端关节弯曲(DA)是一类常染色体显性遗传(Autosomal Dominant,AD)病,具有典型的AD遗传学特征,即每代个体中都有受累患者;患者间无性别差异;在同一家系中,并非所有患者都表现出典型的远端关节挛缩或畸形,存在外显率降低的情况;另外,同一家系中不同患者表型可有明显差异[1]。
目前,国内外对于DA的遗传学研究主要集中在调节肌肉及肌腱形成的相关基因上。骨骼肌收缩、舒张的基本功能单位是肌小节。肌小节由粗肌丝(或称肌球蛋白(Myosin)组成)、细肌丝(或称肌动蛋白(Actin))组成并按一定规律排列而成,肌丝滑行受到两种调节蛋白(原肌凝蛋白(Tropomysin,TPM)和肌钙蛋白(Troponin,TNN))的调控,TPM-TNN-Actin复合物与肌凝蛋白(Myosin)作用控制着肌肉的收缩与舒张[1]。因此,凡是影响肌丝或调节蛋白的因素,都可能对肌肉的收缩、舒张功能造成影响。Naimi等通过构建果蝇TPM-TNN-Actin复合物突变模型,观察到果蝇出现翅膀前伸隆起和肋间肌过度挛缩的表型,这为研究肌肉发育障碍与DA之间的联系提供了可参照的动物模型[2]。在此模型基础上,学者们通过基因测序等方法相继确定了TPM2、TNNI2、TNNT3、MYH3以及FBN2等基因为DA的候选基因[3-7]。其中TPM2编码的蛋白产物为β-原肌凝蛋白,该蛋白存在于快肌纤维中,整体带负电荷,蛋白构象随着周围环境中钙离子浓度的变化而发生改变[8]。Sung等通过对14个DA-1家系的基因测序后发现,患者家系中存在TPM2基因外显子区域的G>C突变,该突变可能导致β-原肌凝蛋白表面负电荷减少,使蛋白构象和弯曲度发生改变,影响了β-原肌凝蛋白与肌凝蛋白的相互作用,并导致肌动-肌凝蛋白-ATP酶复合物对钙离子敏感度的降低,从而最终对肌肉收缩功能造成影响[5]。MYH3基因编码胚胎型肌球蛋白,与TPM2基因编码的β-原肌凝蛋白共同参与快肌纤维的构成。胚胎型肌球蛋白分别由球状的动力区、较短的颈部及铰链样区域以及长卷曲样螺旋的棒状区域所构成。目前已经发现的可引起DA的MYH3基因突变大多参与编码位于该蛋白的球状动力区以及颈部区域的氨基酸,且较集中于球状动力区中ATP结合位点周围。致病突变可能通过影响局部氨基酸链的微结构导致该蛋白ATP激酶活性改变,并最终对骨骼肌收缩能力造成影响[9]。MYH3基因的突变可以解释90%的DA-2型及40%的DA-3型的发生,因此该基因是目前研究DA领域中较为热门的候选基因。
另外,有人试图通过对DA患者进行连锁分析来定位其发病相关的热点区域,目前已经报道了9p13.2-p13.1、11p15.5、5q23-q21等热点区域[6,7,8],上述候选基因大多位于这些连锁区域内,进一步提示这些基因与DA有较强的相关性。
虽然已有不少关于DA致病基因及遗传热点区域的相关报道,但DA具有高度的遗传异质性和基因多效性,即同一亚型的DA可由多种不同的致病基因突变所引起,而同一个致病基因的不同突变可导致不同亚型DA的发生。在Sung等的报道中仅有10%的DA-2b患者存在TNNI2基因突变,在14个DA-1型的先证者中也仅有1名患者检测出TPM2基因错义突变,在散发DA-1型患者中未检出TNNI2和TPM2的突变。另外,MYH3基因突变在DA-1、2、3、8亚型中均有发现,也提示DA中还存在其他的致病基因。
全基因组外显子测序,也称为外显子组测序(exome sequencing),是一种经济的测序方法,其主要是对人类基因组的编码区进行测序,从而探测与罕见和常见疾病相关的新基因。由于该方法只测序全部基因组的编码区(占全部基因组的约1%),因此,该方法相对节省成本,并且伴有较高的覆盖效率和深度。就目前而言,大多数单基因疾病由致病基因的功能变异引起,而大部分的此类功能变异又发生于外显子区域中,因此,全基因组外显子测序被认为是弥补定位克隆技术的重要技术。
全基因组外显子测序技术已被证明为减少稀有单基因疾病的候选基因个数甚至发现其致病基因的有力、有效手段。通过对很少的几个个体(包括患者及正常对照)进行外显子组测序,以筛选与疾病相关的变异,其成功率大为提升。自2009年以来,国内外已经利用全基因组外显子测序技术,成功地发现或验证了一些单基因疾病(Freeman–Sheldon综合征、Miller综合征、Kabuki综合征、BVVL综合征、逆向性痤疮、脊髓小脑共济失调、Schinzel-Giedion综合征、非综合征性耳聋)的致病基因。
发明内容
本发明基于全基因组外显子测序技术以及sanger测序法,成功鉴定出了与DA相关的致病基因—MET基因,以及其中的致病突变(MET基因的杂合变异:
NM000245.1:外显子19:c.3701A→G;p.Y1234C))。在此基础上,本发明提供了突变的MET基因及其用途,包含突变的MET基因的载体、宿主细胞以及试剂盒。此外,本发明还提供了用于诊断的方法,用于所述方法的诊断剂,以及包含所述诊断剂的试剂盒。本发明所鉴定的DA致病基因,为进一步探明该疾病的发病机制奠定了重要基础,并且有可能为患者的治疗方案提供全新的理论依据。此外,本发明所鉴定的DA致病基因还对将来的遗传咨询、产前诊断及基因治疗具有重要意义。另外,在NM_000245(SEQ ID NO:5)这个转录本中,MET基因一共有21个外显子,此次发现的突变(c.3701A→G)位于第19号外显子上。
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的分子遗传学、核酸化学和分子生物学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文中所使用的,术语“MET基因”是指编码肝细胞生长因子受体的基因,具有21个外显子,并且其示例性cDNA序列如SEQ ID NO:1所示,长度为6635bp,翻译出1390个氨基酸。
如本文中所使用的,当用具体的序列来描述基因或核酸时,其不仅包括该具体序列所代表的基因或核酸,而且包括该具体序列的互补序列所代表的基因或核酸。在本申请中,虽然为了方便起见,在多数情况下针对基因或核酸只给出了一条链的序列,然而本领域技术人员可以明确获知其互补链的序列。因此,本申请事实上也公开了所述互补链的序列。
例如,当提及MET基因的cDNA序列时,其不仅包括cDNA的实际序列,而且包括所述实际序列的互补序列。又如,当提及SEQ ID NO:1时,其不仅包括SEQ ID NO:1所示的序列,而且包括SEQ ID NO:1的互补序列。
本申请中的核酸序列包括DNA形式和RNA形式。除非上下文特别指明,否则本发明的核酸序列不仅包括DNA形式,而且包括RNA形式。例如,当提及SEQ ID NO:1时,其不仅包括DNA形式(例如,cDNA序列),而且包括RNA形式(例如,mRNA序列)。
如本文中所使用的,术语“突变”,当用于描述基因或DNA时,是指基因序列或DNA序列中一个或多个(例如,几个)碱基的添加、缺失和/或置换;当用于描述蛋白质时,是指蛋白质氨基酸序列中一个或多个(例如,几个)氨基酸残基的添加、缺失和/或置换。
如本文中所使用的,术语“沉默突变”是指这样的基因突变,其引起mRNA中的密码子发生改变,但由于密码子的简并性而未引起编码的氨基酸发生改变。如本文中所使用的,术语“非沉默突变”是指除了沉默突变以外的基因突变,包括但不限于,错义突变、无义突变和移码突变等。
如本文中所使用的,术语“功能丧失性突变”是指这样的突变,其导致突变基因所编码的蛋白丧失了对应的野生型蛋白的生物学功能,或与对应的野生型蛋白相比,具有异常的生物学功能。
如本文中所使用的,术语“杂合突变”是指这样的突变,其仅存在于一对等位基因中的一个基因中。如本文中所使用的,术语“纯合突变”是指这样的突变,其在一对等位基因中的两个基因中同时存在。
如本文中所使用的,术语“c.3701”是指cDNA序列的第3701位碱基(以起始密码子ATG的碱基A为第1位碱基),其中“c.”表示cDNA,数字“3701”表示第3701碱基。本文中所使用的其他类似的术语具有类似的含义。
如本文中所使用的,术语“p.1234”是指蛋白质序列的第1234位氨基酸残基,其中“p.”表示蛋白质,数字“1234”表示第1234位氨基酸残基。本文中所使用的其他类似的术语具有类似的含义。
如本文中所使用的,术语“c.3701A→G”是指cDNA序列的第3701位碱基(以起始密码子ATG的碱基A为第1位碱基)由A突变为G。本文中所使用的其他类似的术语具有类似的含义。
如本文中所使用的,术语“p.Y1234C”是指蛋白质序列的第1234位氨基酸残基由酪氨酸(Tyr)突变为半胱氨酸(Cys)。本文中所使用的其他类似的术语具有类似的含义。
如本文中所使用的,氨基酸通常用本领域公知的单字母和三字母缩写来表示。例如,丙氨酸可用A或Ala表示。另外,还用“*”表示终止密码子。
如本文中所使用的,术语“载体(vector)”是指,可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时,载体称为表达载体。此类载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌体;柯斯质粒等等。
载体中可包含与目的基因可操作地连接的表达控制序列。如本文中所使用的,术语“可操作地连接”是指所连接的分子的连接方式使得能够实现预期的功能。例如,表达控制序列与基因编码序列的可操作的连接可实现表达控制序列对基因编码序列的表达的控制作用。如本文中所使用的,术语“表达控制序列”是实现基因表达所需要的控制序列,其是本领域熟知的。表达控制序列通常必须包括启动子,常常也包括转录终止序列,并且还可以包含其他序列,如增强子序列。基因表达对于siRNA、miRNA等而言是指转录,并且还可以包括转录后加工;对于蛋白质编码序列而言通常是指转录和翻译,产生蛋白质。
另外,载体中还可包含选择标记。此类选择标记是本领域技术人员熟知的,例如但不限于抗生素抗性基因,例如青霉素抗性基因、红霉素抗性基因等等。
如本文中所使用的,“PCR引物”指用于在PCR反应中扩增靶标核酸的多核苷酸片段,其通常为寡核苷酸,例如含有至少5个碱基,例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、30、35、40、45、50个或者更多个碱基的多核苷酸片段。
本领域技术人员公知,引物不必与待扩增的目的基因或其互补链完全互补,只要其能够特异性扩增目的基因。如本文中所使用的,术语“特异性扩增”是指引物能够通过PCR反应扩增目的基因,而不扩增其他基因。例如,特异性扩增MET基因是指,在PCR反应中引物只扩增MET基因,而不扩增其他基因。此类引物的设计是本领域技术人员公知的。
通常,引物与待扩增的目的基因或其互补链具有大体上的同一性,从而能够特异性扩增目的基因。例如,引物与待扩增的目的基因或其互补链具有至少60%的序列同一性,例如至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性。
如本文中所使用的,术语“同一性”用于指两个多肽之间或两个核酸之间序列的匹配情况。当两个进行比较的序列中的某个位置都被相同的碱基或氨基酸单体亚单元占据时(例如,两个DNA分子的每一个中的某个位置都被腺嘌呤占据,或两个多肽的每一个中的某个位置都被赖氨酸占据),那么各分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如,如果两个序列的10个位置中有6个匹配,那么这两个序列具有60%的同一性。例如,DNA序列CTGACT和CAGGTT共有50%的同一性(总共6个位置中有3个位置匹配)。通常,在将两个序列比对以产生最大同一性时进行比较。这样的比对可通过使用,例如,可通过计算机程序例如Align程序(DNAstar,Inc.)方便地进行的Needleman等人(1970)J.Mol.Biol.48:443-453的方法来实现。
如本文中所使用的,术语“杂交”是指相互间具有互补序列的两个单链核酸分子在一定条件下(适宜的温度及离子强度等)按碱基互补配对原则退火形成双链核酸的过程。核酸杂交可以在DNA-DNA之间,也可在DNA-RNA或RNA-RNA之间进行,只要它们之间存在互补序列,可以进行碱基配对。一般而言,杂交的双方是待测核酸分子和已知核酸分子。在杂交体系中已知的核酸分子称作探针(probe)。核酸杂交包括固-液相杂交和液相杂交。液相杂交是在溶液中进行的杂交反应,其是指待测核酸分子与已知核酸分子(探针)在溶液中退火形成杂交复合物。
如本文中所使用的,术语“特异性检测MET基因突变”是指探针能够区分出含有突变的MET基因与不含有突变的MET基因。一般而言,可以通过控制杂交条件的严紧性,使得探针能够区分出含有突变的基因与不含有突变的基因。例如,在高度严紧条件下,与MET基因精确互补的探针可以与不含有突变的MET基因杂交,而不与甚至只包含一个点突变的MET基因杂交,从而将二者区分开。同样,还可以设计与突变的MET基因精确互补的探针,从而其在高度严紧条件下与突变的MET基因杂交,而不与不含有突变的MET基因杂交。
在分子生物学领域中,探针的设计和杂交技术是熟知的。通常,探针是经标记的,从而在杂交反应结束后,通过利用探针上的标记物,可以分离和检测杂交后的双链。同样,也可以对引物进行标记,从而在PCR后,通过利用引物上的标记物,可以分离和检测扩增产物。可用于标记探针和引物的标记物在本领域内是已知的,包括但不限于,放射性同位素如125I、酶、酶的底物、发光物质如异鲁米诺和吖啶酯、荧光物质如荧光素和罗丹明、生物素和有色物质如乳胶颗粒和胶体金等。
如本文中所使用的,术语“能够特异性识别/结合突变的MET蛋白的抗体或其抗原结合片段”是指这样的抗体或其抗原结合片段,其特异性识别/结合突变的MET蛋白,而不识别或结合野生型MET蛋白。
如本文中所使用的,术语“中和性抗体”是指,能阻断或抑制其所识别的抗原的活性或功能的抗体。
如本文中所使用的,术语“特异性靶向突变的MET基因的siRNA”是指,siRNA能够通过RNA干扰特异性沉默或抑制突变的MET基因的表达,而不影响野生型MET基因的表达。
如本文中所使用的,术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其是本领域公知的并且包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
如本文中所使用的,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如DA)有效量是指,足以预防,阻止,或延迟疾病(例如DA)的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
本发明至少部分基于发明人的发现:MET基因的突变可导致DA。在此基础上,本发明提供了突变的MET基因及其用途,包含突变的MET基因的载体、宿主细胞以及试剂盒。此外,本发明还提供了用于诊断或治疗DA的方法,用于所述方法的诊断剂或治疗剂,以及包含所述诊断剂或治疗剂的试剂盒。
因此,在一个方面,本发明提供了突变的MET基因,其与SEQ ID NO:1相比具有至少1个非沉默突变,并且所述突变的MET基因编码与野生型MET蛋白相比,功能异常(例如丧失了功能)的蛋白,或导致DA的发生。
在一个优选的实施方案中,所述非沉默突变选自添加,缺失和置换中的一种或多种。在一个优选的实施方案中,所述非沉默突变位于MET基因的外显子区域。在一个优选的实施方案中,所述非沉默突变位于MET基因的第19个外显子。在一个优选的实施方案中,所述非沉默突变位于:c.3701。在进一步优选的实施方案中,所述非沉默突变是:c.3701A→G。
在另一个方面,本发明提供了包含上述突变的MET基因的载体。
在一个优选的实施方案中,所述载体包括但不限于克隆载体和表达载体。在一个优选的实施方案中,所述载体是例如质粒,粘粒,噬菌体,柯斯质粒等等。在一个优选的实施方案中,所述载体是商购可得的。在一个优选的实施方案中,所述载体包含与上述突变的MET基因可操作地连接的表达控制序列,例如但不限于启动子,增强子和终止子。在一个优选的实施方案中,所述载体任选地还包含选择标记。
在另一个方面,本发明提供了包含上述突变的MET基因和/或载体的宿主细胞。此类宿主细胞包括但不限于,原核细胞例如大肠杆菌细胞,以及真核细胞例如酵母细胞,昆虫细胞,植物细胞和动物细胞(如哺乳动物细胞,例如小鼠细胞、人细胞等)。本发明的宿主细胞还可以是细胞系,例如293T细胞。
本领域技术人员公知,可将致病基因用于产生疾病动物模型和/或用作药物靶点,从而研究疾病的发病机制和开发有效治疗疾病的药物。因此,在另一个方面,本发明提供了上述突变的MET基因的用途,其用于产生DA动物模型,或用作药物靶点,或用于制备试剂盒,所述试剂盒用于产生DA动物模型,或用作药物靶点。
在一个优选的实施方案中,所述动物包括但不限于,哺乳动物,例如小鼠,大鼠,兔和猴。
在另一个方面,本发明提供了上述载体或宿主细胞的用途,其用于产生DA动物模型,或用于制备试剂盒,所述试剂盒用于产生DA动物模型。
在另一个方面,本发明提供了试剂盒,其包含上述突变的MET基因和/或载体和/或宿主细胞。
在另一个方面,本发明提供了用于诊断DA的诊断剂,其包含能够特异性扩增MET基因或其片段的引物,或能够特异性检测MET基因突变的探针,或能够特异性识别突变的MET蛋白的抗体或其抗原结合片段。
在一个优选的实施方案中,所述引物能够特异性扩增MET基因的外显子,优选第19个外显子。在一个优选的实施方案中,所述MET基因突变位于MET基因的外显子,优选第19个外显子,更优选地位于:c.3701。在进一步优选的实施方案中,所述突变是c.3701A→G。在一个优选的实施方案中,所述突变的MET蛋白包含氨基酸突变p.Y1234C。在一个优选的实施方案中,所述引物、探针或抗体或其抗原结合片段是经标记的。优选地,能够特异性扩增MET基因的第19个外显子的引物的核苷酸序列如SEQ ID NO:2和3所示,其中,
正向引物:5’-ATTTATTTGATGAGGCCGATGT-3’(SEQ ID NO:2);
反向引物:5’-CTAATGAGGGCTCTGAGGGA-3’(SEQ ID NO:3)。
在另一个方面,本发明提供了试剂盒,其包含上文所述的诊断剂。
在一个优选的实施方案中,所述试剂盒还包含其他试剂,例如用于PCR的试剂(例如dNTP和聚合酶),用于提取核酸的试剂,用于检测所述抗体或其抗原结合片段的二抗等。
在另一个方面,本发明提供了用于治疗DA的治疗剂,其包含分离的正常的MET基因,或含有所述基因的载体,或具有正常生物学功能的MET蛋白,或特异性靶向突变的MET基因的siRNA,或特异性结合突变的MET蛋白的中和性抗体。如本文中所使用的,术语“正常的MET基因”是指编码具有正常生物学功能的MET蛋白的MET基因,其例如但不限于,如SEQ IDNO:1所示的MET基因。
在一个优选的实施方案中,所述突变的MET基因所包含的突变位于MET基因的外显子,优选第19个外显子,更优选地位于:c.3701。在进一步优选的实施方案中,所述突变是c.3701A→G。在一个优选的实施方案中,所述突变的MET蛋白包含氨基酸突变p.Y1234C。其中,突变的MET蛋白的氨基酸序列如SEQ ID NO:4所示。
在另一个方面,本发明提供了一种药物组合物,其包含上文所述的治疗剂,和药学上可接受的载体和/或赋形剂。
在另一个方面,本发明提供了诊断受试者是否患有DA或处于发展DA的风险中的方法,其包括,检测受试者的MET基因是否存在非沉默突变,如果存在所述非沉默突变,则判断受试者患有DA或处于发展DA的风险中。
在一个优选的实施方案中,所述非沉默突变选自添加,缺失和置换中的一种或多种。在一个优选的实施方案中,所述非沉默突变位于MET基因的外显子区域。在一个优选的实施方案中,所述非沉默突变位于MET基因的第19个外显子。在一个优选的实施方案中,所述非沉默突变位于c.3701。在一个优选的实施方案中,所述非沉默突变是c.3701A→G。
在另一个方面,本发明提供了诊断受试者是否患有DA或处于发展DA的风险中的方法,其包括:
1)获得来自所述受试者的核酸样品(例如,基因组DNA样品或总mRNA样品);
2)在所述核酸样品中确定MET基因中是否存在导致MET基因编码功能异常的蛋白的非沉默突变;和
3)如果存在所述非沉默突变,则判断受试者患有DA或处于发展DA的风险中。
在一个优选的实施方案中,所述非沉默突变选自添加,缺失和置换中的一种或多种。在一个优选的实施方案中,所述非沉默突变位于MET基因的外显子区域。在一个优选的实施方案中,所述非沉默突变位于MET基因的第19个外显子。在一个优选的实施方案中,所述非沉默突变位于c.3701。在一个优选的实施方案中,所述非沉默突变是c.3701A→G。
在另一个方面,本发明提供了检测MET基因的突变的方法,其包括使用上文所述的诊断剂。
在一个优选的实施方案中,所述方法不是诊断方法。例如,所述方法可以用于研究目的。
在另一个方面,本发明提供了治疗受试者的DA的方法,其包括给有此需要的受试者施用有效量的上文所述的治疗剂。
在另一个方面,本发明提供了上文所述的诊断剂在制备用于检测MET基因的突变和/或用于诊断DA的试剂盒中的用途。
在另一个方面,本发明提供了上文所述的治疗剂在制备用于治疗DA的药物组合物中的用途。
本发明的试剂、试剂组合物、药物组合物或试剂盒中可进一步包含与活性成分相容的缓冲液、载体或媒介等,例如选自下列的一种或多种:水、生理盐水、磷酸缓冲液、左旋糖、甘油、乙醇和其他类似物,以及上述物质的组合。此类缓冲液、载体或媒介可进一步包括微量辅助物质,例如湿润剂、乳化剂、表面活性剂、防腐剂或助悬剂等。
本发明的有益效果:
本发明通过外显子组测序技术确定了DA的致病基因,这至少带来了以下有益效果。
一方面,本发明为DA的诊断和治疗提供了新的方法和工具。特别地,本发明所提供的诊断方法以及用于该方法的引物和/或探针和/或抗体可用于快速、有效地确定受试者是否患有DA或处于发展DA的风险中。
另一方面,本发明为DA的发病机制研究奠定了重要基础,为DA患者的治疗提供全新的理论依据。另外,DA的致病基因的鉴定对将来的遗传咨询、产前诊断及基因治疗具有重要意义。此外,利用DA致病基因所获得的疾病动物模型是研究DA的发病机制和治疗方法的有力工具。
附图说明
图1展示了实施例1中所使用的DA家系的家系图谱;其中,○表示正常女性;□表示正常男性;■表示男性患者;●表示女性患者,“/”表示去世,对Ⅱ14、Ⅲ14、Ⅲ16、Ⅲ22和Ⅳ8受试者的样品进行了全基因组外显子测序,“AA\AG”表示使用Sanger测序法对来自该受试者的样品进行了家系内点验证的结果;
图2为DA患者家系的手部外观图;
图3为DA患者家系的手部X线检查结果图;
图4为手部畸形矫形术患者的病变部位H-E染色结果;
图5为DA家系正常人和患者的MET基因的sanger测序结果;
图6为MET基因在各组织中的表达量;
图7中为基于突变后的MET基因预测的所编码的蛋白整体结构表面图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,下面将结合附图和具体实施例对本发明作进一步说明。
除非特别指明,否则基本上按照本领域内熟知的以及在各种参考文献中描述的常规方法进行实施例中描述的实验和方法(例如,分子生物学和核酸化学实验方法)。参见例如,Sambrook等人,Molecular Cloning:A Laboratory Manual,第2版,Cold SpringHarborLaboratory Press,Cold Spring Harbor,N.Y.(1989);和Ausubel等人,CurrentProtocolsin Molecular Biology,Greene Publishing Associates(1992),其全部通过引用合并入本文。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。本领域技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本发明所要求保护的范围。
实施例1 DA-1型家系标本收集、影像学及组织学检查
(1)本申请的发明人通过在广东省内组织开展DA家系的病例收集,收集到一个包括12名患者在内的四代共54人的DA-1型大家系(如图1所示),根据家系成员的远端关节的外观(如图2所示)及X片表现(如图3所示)明确DA诊断,并依据Bamshad与Hall建立的诊断标准对患者进行分类。
结果分析:
从图1可知,该家系包含4代共54名家庭成员,其中患者占12人,遗传符合常染色体显性遗传规律;
从图2可知,患者主要表现为指间关节弯曲、屈指间隙消失及腕关节尺侧偏移,以上三个症状均为远端关节弯曲-1型的典型症状。患者除上肢受累外,并无颜面部及其他部位受累,因此可以排除远端关节弯曲其他亚型的诊断;
从图3可知,患者手部X线显示患者骨骼无受累。
(2)收集已进行手部畸形矫形术患者的病变部位的软骨、肌肉、皮肤、囊腔等组织,并对组织进行病理活检及H-E染色观察,明确病变所累及的组织及病变类型。
结果分析:如图4所示,与年龄及性别匹配的正常对照(con)相比,患者的肌肉组织出现了明显的肌纤维大小不一,并伴随有新生/坏死的肌纤维细胞(黑色箭头所指),以上结果均提示患者存在肌肉组织的病变。
实施例2 DA-1型家系中致病基因的定位及预测突变可能产生的功能影响
(1)全基因组外显子测序
根据远端关节弯曲的疾病特点(遗传背景、AT含量、重复序列组成及杂合度等),采用Agilent SureSelectXT Human All Exon kit进行捕获建库,完成对已收集到家系中的4名DA-1型患者及1名正常人的全基因组外显子测序。测序采用平台为HiSeq PE150,每个样本平均数据量高于10G RAW Data,产生的测序数据结果如表1和2所示。
表1 DA-1大家系全基因组外显子测序的深度及覆盖度数据
表2 DA-1型大家系全基因组外显子测序突变类型及数目
结果与分析:
从表1可知,本次测序选取了图1家系中的II:14,III:14,III:16,III:22以及IV:85名成员进行了全基因组外显子测序,针对外显子区域的测序深度均在149*以上,测序的覆盖度均在99.8%以上,以上结果表明此次全基因组外显子测序能够对目标的外显子区域进行很好的覆盖及测序,测序结果可以用于后续的基因分析。
从表2可知,通过对5名家庭成员的全基因组外显子测序数据进行分析后发现,此次测序中的突变大部分分布在外显子区域,同时有部分突变位于内含子及基因的3’及5’段以及基因与基因之间;通过对突变可能产生的影响进行分析,发现突变可分为同义突变,错义突变,无义突变及终止密码子缺失突变,附表中显示了每位成员测序结果中各类突变的数量。
(2)Sanger测序
针对全基因组外显子测序所得到的可能突变位点设计扩增引物序列,其中,针对MET基因第19号外显子的扩增引物对如SEQ ID NO:2和3所示;并在家系中22受试者对上述位点进行Sanger测序,选取其中共分离的位点(即家系中每一位患者均携带该突变,而每一位正常人均不携带该突变);
从图1可知,该DA家系中22受试者中,10个患者都存在相同的错意突变(c.3701A→G),而12个家系内正常对照中,均不存在此突变。也即,所述错义突变在DA家系内表现为与疾病共分离。图5示例性显示了患者和正常人的MET基因的测序结果,其中患者具有杂合的c.3701A→G(相应的氨基酸突变为p.Y1234C)突变,而正常人不具有该突变(即,在c.3701处具有纯合的碱基A)。
因此,所获得的测序结果充分表明,本发明所鉴定到的杂合突变导致MET蛋白的结构和功能发生变化,从而导致DA疾病。即,MET基因为DA的致病基因,该基因的突变与DA疾病的发生具有相关性。
(3)MET基因点突变对其编码蛋白功能及结构影响的预测
利用polyPhen2、SIFT、Mutation Taster、phostcon等软件和数据库,对突变位点可能对蛋白功能造成的影响进行预测(如表3所示),并构建MET基因点突变后所编码的蛋白结构,结合上述结果综合分析点突变对MET蛋白结构与功能可能造成的影响。
图7为基于软件预测突变后的MET基因所编码的蛋白整体结构表面图。其中,白色为疏水残基,绿色为极性残基,蓝色为带正电残基。其中MET基因点突变所参与编码的氨基酸用Licorice方式显示其原子结构,红色为突变体,蓝色为野生型。
结果分析:结合图7和表3,可以得知,MET基因的c.3701为高度保守的位点,并且该错义突变被Mutation Taster软件预测为“破坏性(damaging)”的突变,被PolyPhen2软件预测为“可能破坏性(probably damaging)”的突变。如图6所示,MET基因在各组织中的表达情况检测,检测发现MET基因在肌肉,肾脏,肝脏,子宫,软骨组织中表达程度较高。
由此,这些结果有力地支持了我们的结论:MET基因为DA的致病基因,该基因中的非沉默突变将导致DA疾病的发生。另外,MET基因在GERP数据库以及在PHASTCONS数据库中均有很高评分,说明该基因在进化中具有高度保守性,提示MET基因具有重要功能。
表3基于各大数据库对MET基因点突变可能引起的功能性改变做出预测
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
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SEQUENCE LISTING
<110> 中山大学附属第一医院
<120> 远端关节弯曲病的致病基因及其用途
<130> 2017
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 6635
<212> DNA
<213> 智人
<400> 1
aggtgacccg gaggccctcg ccgcccgcgg cgccccgagc gctttgtgag cagatgcgga 60
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gaggcgcgga gcgcgcgtgt ggtccttgcg ccgctgactt ctccactggt tcctgggcac 180
cgaaagataa acctctcata atgaaggccc ccgctgtgct tgcacctggc atcctcgtgc 240
tcctgtttac cttggtgcag aggagcaatg gggagtgtaa agaggcacta gcaaagtccg 300
agatgaatgt gaatatgaag tatcagcttc ccaacttcac cgcggaaaca cccatccaga 360
atgtcattct acatgagcat cacattttcc ttggtgccac taactacatt tatgttttaa 420
atgaggaaga ccttcagaag gttgctgagt acaagactgg gcctgtgctg gaacacccag 480
attgtttccc atgtcaggac tgcagcagca aagccaattt atcaggaggt gtttggaaag 540
ataacatcaa catggctcta gttgtcgaca cctactatga tgatcaactc attagctgtg 600
gcagcgtcaa cagagggacc tgccagcgac atgtctttcc ccacaatcat actgctgaca 660
tacagtcgga ggttcactgc atattctccc cacagataga agagcccagc cagtgtcctg 720
actgtgtggt gagcgccctg ggagccaaag tcctttcatc tgtaaaggac cggttcatca 780
acttctttgt aggcaatacc ataaattctt cttatttccc agatcatcca ttgcattcga 840
tatcagtgag aaggctaaag gaaacgaaag atggttttat gtttttgacg gaccagtcct 900
acattgatgt tttacctgag ttcagagatt cttaccccat taagtatgtc catgcctttg 960
aaagcaacaa ttttatttac ttcttgacgg tccaaaggga aactctagat gctcagactt 1020
ttcacacaag aataatcagg ttctgttcca taaactctgg attgcattcc tacatggaaa 1080
tgcctctgga gtgtattctc acagaaaaga gaaaaaagag atccacaaag aaggaagtgt 1140
ttaatatact tcaggctgcg tatgtcagca agcctggggc ccagcttgct agacaaatag 1200
gagccagcct gaatgatgac attcttttcg gggtgttcgc acaaagcaag ccagattctg 1260
ccgaaccaat ggatcgatct gccatgtgtg cattccctat caaatatgtc aacgacttct 1320
tcaacaagat cgtcaacaaa aacaatgtga gatgtctcca gcatttttac ggacccaatc 1380
atgagcactg ctttaatagg acacttctga gaaattcatc aggctgtgaa gcgcgccgtg 1440
atgaatatcg aacagagttt accacagctt tgcagcgcgt tgacttattc atgggtcaat 1500
tcagcgaagt cctcttaaca tctatatcca ccttcattaa aggagacctc accatagcta 1560
atcttgggac atcagagggt cgcttcatgc aggttgtggt ttctcgatca ggaccatcaa 1620
cccctcatgt gaattttctc ctggactccc atccagtgtc tccagaagtg attgtggagc 1680
atacattaaa ccaaaatggc tacacactgg ttatcactgg gaagaagatc acgaagatcc 1740
cattgaatgg cttgggctgc agacatttcc agtcctgcag tcaatgcctc tctgccccac 1800
cctttgttca gtgtggctgg tgccacgaca aatgtgtgcg atcggaggaa tgcctgagcg 1860
ggacatggac tcaacagatc tgtctgcctg caatctacaa ggttttccca aatagtgcac 1920
cccttgaagg agggacaagg ctgaccatat gtggctggga ctttggattt cggaggaata 1980
ataaatttga tttaaagaaa actagagttc tccttggaaa tgagagctgc accttgactt 2040
taagtgagag cacgatgaat acattgaaat gcacagttgg tcctgccatg aataagcatt 2100
tcaatatgtc cataattatt tcaaatggcc acgggacaac acaatacagt acattctcct 2160
atgtggatcc tgtaataaca agtatttcgc cgaaatacgg tcctatggct ggtggcactt 2220
tacttacttt aactggaaat tacctaaaca gtgggaattc tagacacatt tcaattggtg 2280
gaaaaacatg tactttaaaa agtgtgtcaa acagtattct tgaatgttat accccagccc 2340
aaaccatttc aactgagttt gctgttaaat tgaaaattga cttagccaac cgagagacaa 2400
gcatcttcag ttaccgtgaa gatcccattg tctatgaaat tcatccaacc aaatctttta 2460
ttagtggtgg gagcacaata acaggtgttg ggaaaaacct gaattcagtt agtgtcccga 2520
gaatggtcat aaatgtgcat gaagcaggaa ggaactttac agtggcatgt caacatcgct 2580
ctaattcaga gataatctgt tgtaccactc cttccctgca acagctgaat ctgcaactcc 2640
ccctgaaaac caaagccttt ttcatgttag atgggatcct ttccaaatac tttgatctca 2700
tttatgtaca taatcctgtg tttaagcctt ttgaaaagcc agtgatgatc tcaatgggca 2760
atgaaaatgt actggaaatt aagggaaatg atattgaccc tgaagcagtt aaaggtgaag 2820
tgttaaaagt tggaaataag agctgtgaga atatacactt acattctgaa gccgttttat 2880
gcacggtccc caatgacctg ctgaaattga acagcgagct aaatatagag tggaagcaag 2940
caatttcttc aaccgtcctt ggaaaagtaa tagttcaacc agatcagaat ttcacaggat 3000
tgattgctgg tgttgtctca atatcaacag cactgttatt actacttggg tttttcctgt 3060
ggctgaaaaa gagaaagcaa attaaagatc tgggcagtga attagttcgc tacgatgcaa 3120
gagtacacac tcctcatttg gataggcttg taagtgcccg aagtgtaagc ccaactacag 3180
aaatggtttc aaatgaatct gtagactacc gagctacttt tccagaagat cagtttccta 3240
attcatctca gaacggttca tgccgacaag tgcagtatcc tctgacagac atgtccccca 3300
tcctaactag tggggactct gatatatcca gtccattact gcaaaatact gtccacattg 3360
acctcagtgc tctaaatcca gagctggtcc aggcagtgca gcatgtagtg attgggccca 3420
gtagcctgat tgtgcatttc aatgaagtca taggaagagg gcattttggt tgtgtatatc 3480
atgggacttt gttggacaat gatggcaaga aaattcactg tgctgtgaaa tccttgaaca 3540
gaatcactga cataggagaa gtttcccaat ttctgaccga gggaatcatc atgaaagatt 3600
ttagtcatcc caatgtcctc tcgctcctgg gaatctgcct gcgaagtgaa gggtctccgc 3660
tggtggtcct accatacatg aaacatggag atcttcgaaa tttcattcga aatgagactc 3720
ataatccaac tgtaaaagat cttattggct ttggtcttca agtagccaaa ggcatgaaat 3780
atcttgcaag caaaaagttt gtccacagag acttggctgc aagaaactgt atgctggatg 3840
aaaaattcac agtcaaggtt gctgattttg gtcttgccag agacatgtat gataaagaat 3900
actatagtgt acacaacaaa acaggtgcaa agctgccagt gaagtggatg gctttggaaa 3960
gtctgcaaac tcaaaagttt accaccaagt cagatgtgtg gtcctttggc gtgctcctct 4020
gggagctgat gacaagagga gccccacctt atcctgacgt aaacaccttt gatataactg 4080
tttacttgtt gcaagggaga agactcctac aacccgaata ctgcccagac cccttatatg 4140
aagtaatgct aaaatgctgg caccctaaag ccgaaatgcg cccatccttt tctgaactgg 4200
tgtcccggat atcagcgatc ttctctactt tcattgggga gcactatgtc catgtgaacg 4260
ctacttatgt gaacgtaaaa tgtgtcgctc cgtatccttc tctgttgtca tcagaagata 4320
acgctgatga tgaggtggac acacgaccag cctccttctg ggagacatca tagtgctagt 4380
actatgtcaa agcaacagtc cacactttgt ccaatggttt tttcactgcc tgacctttaa 4440
aaggccatcg atattctttg ctcttgccaa aattgcacta ttataggact tgtattgtta 4500
tttaaattac tggattctaa ggaatttctt atctgacaga gcatcagaac cagaggcttg 4560
gtcccacagg ccacggacca atggcctgca gccgtgacaa cactcctgtc atattggagt 4620
ccaaaacttg aattctgggt tgaatttttt aaaaatcagg taccacttga tttcatatgg 4680
gaaattgaag caggaaatat tgagggcttc ttgatcacag aaaactcaga agagatagta 4740
atgctcagga caggagcggc agccccagaa caggccactc atttagaatt ctagtgtttc 4800
aaaacacttt tgtgtgttgt atggtcaata acatttttca ttactgatgg tgtcattcac 4860
ccattaggta aacattccct tttaaatgtt tgtttgtttt ttgagacagg atctcactct 4920
gttgccaggg ctgtagtgca gtggtgtgat catagctcac tgcaacctcc acctcccagg 4980
ctcaagcctc ccgaatagct gggactacag gcgcacacca ccatccccgg ctaatttttg 5040
tattttttgt agagacgggg ttttgccatg ttgccaaggc tggtttcaaa ctcctggact 5100
caagaaatcc acccacctca gcctcccaaa gtgctaggat tacaggcatg agccactgcg 5160
cccagccctt ataaattttt gtatagacat tcctttggtt ggaagaatat ttataggcaa 5220
tacagtcaaa gtttcaaaat agcatcacac aaaacatgtt tataaatgaa caggatgtaa 5280
tgtacataga tgacattaag aaaatttgta tgaaataatt tagtcatcat gaaatattta 5340
gttgtcatat aaaaacccac tgtttgagaa tgatgctact ctgatctaat gaatgtgaac 5400
atgtagatgt tttgtgtgta tttttttaaa tgaaaactca aaataagaca agtaatttgt 5460
tgataaatat ttttaaagat aactcagcat gtttgtaaag caggatacat tttactaaaa 5520
ggttcattgg ttccaatcac agctcatagg tagagcaaag aaagggtgga tggattgaaa 5580
agattagcct ctgtctcggt ggcaggttcc cacctcgcaa gcaattggaa acaaaacttt 5640
tggggagttt tattttgcat tagggtgtgt tttatgttaa gcaaaacata ctttagaaac 5700
aaatgaaaaa ggcaattgaa aatcccagct atttcaccta gatggaatag ccaccctgag 5760
cagaactttg tgatgcttca ttctgtggaa ttttgtgctt gctactgtat agtgcatgtg 5820
gtgtaggtta ctctaactgg ttttgtcgac gtaaacattt aaagtgttat attttttata 5880
aaaatgttta tttttaatga tatgagaaaa attttgttag gccacaaaaa cactgcactg 5940
tgaacatttt agaaaaggta tgtcagactg ggattaatga cagcatgatt ttcaatgact 6000
gtaaattgcg ataaggaaat gtactgattg ccaatacacc ccaccctcat tacatcatca 6060
ggacttgaag ccaagggtta acccagcaag ctacaaagag ggtgtgtcac actgaaactc 6120
aatagttgag tttggctgtt gttgcaggaa aatgattata actaaaagct ctctgatagt 6180
gcagagactt accagaagac acaaggaatt gtactgaaga gctattacaa tccaaatatt 6240
gccgtttcat aaatgtaata agtaatacta attcacagag tattgtaaat ggtggatgac 6300
aaaagaaaat ctgctctgtg gaaagaaaga actgtctcta ccagggtcaa gagcatgaac 6360
gcatcaatag aaagaactcg gggaaacatc ccatcaacag gactacacac ttgtatatac 6420
attcttgaga acactgcaat gtgaaaatca cgtttgctat ttataaactt gtccttagat 6480
taatgtgtct ggacagattg tgggagtaag tgattcttct aagaattaga tacttgtcac 6540
tgcctatacc tgcagctgaa ctgaatggta cttcgtatgt taatagttgt tctgataaat 6600
catgcaatta aagtaaagtg atgcaacatc ttgta 6635
<210> 2
<211> 22
<212> DNA
<213> 人工序列
<400> 2
atttatttga tgaggccgat gt 22
<210> 3
<211> 20
<212> DNA
<213> 人工序列
<400> 3
ctaatgaggg ctctgaggga 20
<210> 4
<211> 1390
<212> PRT
<213> 智人
<400> 4
Met Lys Ala Pro Ala Val Leu Ala Pro Gly Ile Leu Val Leu Leu Phe
1 5 10 15
Thr Leu Val Gln Arg Ser Asn Gly Glu Cys Lys Glu Ala Leu Ala Lys
20 25 30
Ser Glu Met Asn Val Asn Met Lys Tyr Gln Leu Pro Asn Phe Thr Ala
35 40 45
Glu Thr Pro Ile Gln Asn Val Ile Leu His Glu His His Ile Phe Leu
50 55 60
Gly Ala Thr Asn Tyr Ile Tyr Val Leu Asn Glu Glu Asp Leu Gln Lys
65 70 75 80
Val Ala Glu Tyr Lys Thr Gly Pro Val Leu Glu His Pro Asp Cys Phe
85 90 95
Pro Cys Gln Asp Cys Ser Ser Lys Ala Asn Leu Ser Gly Gly Val Trp
100 105 110
Lys Asp Asn Ile Asn Met Ala Leu Val Val Asp Thr Tyr Tyr Asp Asp
115 120 125
Gln Leu Ile Ser Cys Gly Ser Val Asn Arg Gly Thr Cys Gln Arg His
130 135 140
Val Phe Pro His Asn His Thr Ala Asp Ile Gln Ser Glu Val His Cys
145 150 155 160
Ile Phe Ser Pro Gln Ile Glu Glu Pro Ser Gln Cys Pro Asp Cys Val
165 170 175
Val Ser Ala Leu Gly Ala Lys Val Leu Ser Ser Val Lys Asp Arg Phe
180 185 190
Ile Asn Phe Phe Val Gly Asn Thr Ile Asn Ser Ser Tyr Phe Pro Asp
195 200 205
His Pro Leu His Ser Ile Ser Val Arg Arg Leu Lys Glu Thr Lys Asp
210 215 220
Gly Phe Met Phe Leu Thr Asp Gln Ser Tyr Ile Asp Val Leu Pro Glu
225 230 235 240
Phe Arg Asp Ser Tyr Pro Ile Lys Tyr Val His Ala Phe Glu Ser Asn
245 250 255
Asn Phe Ile Tyr Phe Leu Thr Val Gln Arg Glu Thr Leu Asp Ala Gln
260 265 270
Thr Phe His Thr Arg Ile Ile Arg Phe Cys Ser Ile Asn Ser Gly Leu
275 280 285
His Ser Tyr Met Glu Met Pro Leu Glu Cys Ile Leu Thr Glu Lys Arg
290 295 300
Lys Lys Arg Ser Thr Lys Lys Glu Val Phe Asn Ile Leu Gln Ala Ala
305 310 315 320
Tyr Val Ser Lys Pro Gly Ala Gln Leu Ala Arg Gln Ile Gly Ala Ser
325 330 335
Leu Asn Asp Asp Ile Leu Phe Gly Val Phe Ala Gln Ser Lys Pro Asp
340 345 350
Ser Ala Glu Pro Met Asp Arg Ser Ala Met Cys Ala Phe Pro Ile Lys
355 360 365
Tyr Val Asn Asp Phe Phe Asn Lys Ile Val Asn Lys Asn Asn Val Arg
370 375 380
Cys Leu Gln His Phe Tyr Gly Pro Asn His Glu His Cys Phe Asn Arg
385 390 395 400
Thr Leu Leu Arg Asn Ser Ser Gly Cys Glu Ala Arg Arg Asp Glu Tyr
405 410 415
Arg Thr Glu Phe Thr Thr Ala Leu Gln Arg Val Asp Leu Phe Met Gly
420 425 430
Gln Phe Ser Glu Val Leu Leu Thr Ser Ile Ser Thr Phe Ile Lys Gly
435 440 445
Asp Leu Thr Ile Ala Asn Leu Gly Thr Ser Glu Gly Arg Phe Met Gln
450 455 460
Val Val Val Ser Arg Ser Gly Pro Ser Thr Pro His Val Asn Phe Leu
465 470 475 480
Leu Asp Ser His Pro Val Ser Pro Glu Val Ile Val Glu His Thr Leu
485 490 495
Asn Gln Asn Gly Tyr Thr Leu Val Ile Thr Gly Lys Lys Ile Thr Lys
500 505 510
Ile Pro Leu Asn Gly Leu Gly Cys Arg His Phe Gln Ser Cys Ser Gln
515 520 525
Cys Leu Ser Ala Pro Pro Phe Val Gln Cys Gly Trp Cys His Asp Lys
530 535 540
Cys Val Arg Ser Glu Glu Cys Leu Ser Gly Thr Trp Thr Gln Gln Ile
545 550 555 560
Cys Leu Pro Ala Ile Tyr Lys Val Phe Pro Asn Ser Ala Pro Leu Glu
565 570 575
Gly Gly Thr Arg Leu Thr Ile Cys Gly Trp Asp Phe Gly Phe Arg Arg
580 585 590
Asn Asn Lys Phe Asp Leu Lys Lys Thr Arg Val Leu Leu Gly Asn Glu
595 600 605
Ser Cys Thr Leu Thr Leu Ser Glu Ser Thr Met Asn Thr Leu Lys Cys
610 615 620
Thr Val Gly Pro Ala Met Asn Lys His Phe Asn Met Ser Ile Ile Ile
625 630 635 640
Ser Asn Gly His Gly Thr Thr Gln Tyr Ser Thr Phe Ser Tyr Val Asp
645 650 655
Pro Val Ile Thr Ser Ile Ser Pro Lys Tyr Gly Pro Met Ala Gly Gly
660 665 670
Thr Leu Leu Thr Leu Thr Gly Asn Tyr Leu Asn Ser Gly Asn Ser Arg
675 680 685
His Ile Ser Ile Gly Gly Lys Thr Cys Thr Leu Lys Ser Val Ser Asn
690 695 700
Ser Ile Leu Glu Cys Tyr Thr Pro Ala Gln Thr Ile Ser Thr Glu Phe
705 710 715 720
Ala Val Lys Leu Lys Ile Asp Leu Ala Asn Arg Glu Thr Ser Ile Phe
725 730 735
Ser Tyr Arg Glu Asp Pro Ile Val Tyr Glu Ile His Pro Thr Lys Ser
740 745 750
Phe Ile Ser Gly Gly Ser Thr Ile Thr Gly Val Gly Lys Asn Leu Asn
755 760 765
Ser Val Ser Val Pro Arg Met Val Ile Asn Val His Glu Ala Gly Arg
770 775 780
Asn Phe Thr Val Ala Cys Gln His Arg Ser Asn Ser Glu Ile Ile Cys
785 790 795 800
Cys Thr Thr Pro Ser Leu Gln Gln Leu Asn Leu Gln Leu Pro Leu Lys
805 810 815
Thr Lys Ala Phe Phe Met Leu Asp Gly Ile Leu Ser Lys Tyr Phe Asp
820 825 830
Leu Ile Tyr Val His Asn Pro Val Phe Lys Pro Phe Glu Lys Pro Val
835 840 845
Met Ile Ser Met Gly Asn Glu Asn Val Leu Glu Ile Lys Gly Asn Asp
850 855 860
Ile Asp Pro Glu Ala Val Lys Gly Glu Val Leu Lys Val Gly Asn Lys
865 870 875 880
Ser Cys Glu Asn Ile His Leu His Ser Glu Ala Val Leu Cys Thr Val
885 890 895
Pro Asn Asp Leu Leu Lys Leu Asn Ser Glu Leu Asn Ile Glu Trp Lys
900 905 910
Gln Ala Ile Ser Ser Thr Val Leu Gly Lys Val Ile Val Gln Pro Asp
915 920 925
Gln Asn Phe Thr Gly Leu Ile Ala Gly Val Val Ser Ile Ser Thr Ala
930 935 940
Leu Leu Leu Leu Leu Gly Phe Phe Leu Trp Leu Lys Lys Arg Lys Gln
945 950 955 960
Ile Lys Asp Leu Gly Ser Glu Leu Val Arg Tyr Asp Ala Arg Val His
965 970 975
Thr Pro His Leu Asp Arg Leu Val Ser Ala Arg Ser Val Ser Pro Thr
980 985 990
Thr Glu Met Val Ser Asn Glu Ser Val Asp Tyr Arg Ala Thr Phe Pro
995 1000 1005
Glu Asp Gln Phe Pro Asn Ser Ser Gln Asn Gly Ser Cys Arg Gln
1010 1015 1020
Val Gln Tyr Pro Leu Thr Asp Met Ser Pro Ile Leu Thr Ser Gly
1025 1030 1035
Asp Ser Asp Ile Ser Ser Pro Leu Leu Gln Asn Thr Val His Ile
1040 1045 1050
Asp Leu Ser Ala Leu Asn Pro Glu Leu Val Gln Ala Val Gln His
1055 1060 1065
Val Val Ile Gly Pro Ser Ser Leu Ile Val His Phe Asn Glu Val
1070 1075 1080
Ile Gly Arg Gly His Phe Gly Cys Val Tyr His Gly Thr Leu Leu
1085 1090 1095
Asp Asn Asp Gly Lys Lys Ile His Cys Ala Val Lys Ser Leu Asn
1100 1105 1110
Arg Ile Thr Asp Ile Gly Glu Val Ser Gln Phe Leu Thr Glu Gly
1115 1120 1125
Ile Ile Met Lys Asp Phe Ser His Pro Asn Val Leu Ser Leu Leu
1130 1135 1140
Gly Ile Cys Leu Arg Ser Glu Gly Ser Pro Leu Val Val Leu Pro
1145 1150 1155
Tyr Met Lys His Gly Asp Leu Arg Asn Phe Ile Arg Asn Glu Thr
1160 1165 1170
His Asn Pro Thr Val Lys Asp Leu Ile Gly Phe Gly Leu Gln Val
1175 1180 1185
Ala Lys Gly Met Lys Tyr Leu Ala Ser Lys Lys Phe Val His Arg
1190 1195 1200
Asp Leu Ala Ala Arg Asn Cys Met Leu Asp Glu Lys Phe Thr Val
1205 1210 1215
Lys Val Ala Asp Phe Gly Leu Ala Arg Asp Met Tyr Asp Lys Glu
1220 1225 1230
Cys Tyr Ser Val His Asn Lys Thr Gly Ala Lys Leu Pro Val Lys
1235 1240 1245
Trp Met Ala Leu Glu Ser Leu Gln Thr Gln Lys Phe Thr Thr Lys
1250 1255 1260
Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Leu Met Thr
1265 1270 1275
Arg Gly Ala Pro Pro Tyr Pro Asp Val Asn Thr Phe Asp Ile Thr
1280 1285 1290
Val Tyr Leu Leu Gln Gly Arg Arg Leu Leu Gln Pro Glu Tyr Cys
1295 1300 1305
Pro Asp Pro Leu Tyr Glu Val Met Leu Lys Cys Trp His Pro Lys
1310 1315 1320
Ala Glu Met Arg Pro Ser Phe Ser Glu Leu Val Ser Arg Ile Ser
1325 1330 1335
Ala Ile Phe Ser Thr Phe Ile Gly Glu His Tyr Val His Val Asn
1340 1345 1350
Ala Thr Tyr Val Asn Val Lys Cys Val Ala Pro Tyr Pro Ser Leu
1355 1360 1365
Leu Ser Ser Glu Asp Asn Ala Asp Asp Glu Val Asp Thr Arg Pro
1370 1375 1380
Ala Ser Phe Trp Glu Thr Ser
1385 1390
<210> 5
<211> 6656
<212> DNA
<213> 智人
<400> 5
gcaggtgacc cggaggccct cgccgcccgc ggcgccccga gcgctttgtg agcagatgcg 60
gagccgagtg gagggcgcga gccagatgcg gggcgacagc tgacttgctg agaggaggcg 120
gggaggcgcg gagcgcgcgt gtggtccttg cgccgctgac ttctccactg gttcctgggc 180
accgaaagat aaacctctca taatgaaggc ccccgctgtg cttgcacctg gcatcctcgt 240
gctcctgttt accttggtgc agaggagcaa tggggagtgt aaagaggcac tagcaaagtc 300
cgagatgaat gtgaatatga agtatcagct tcccaacttc accgcggaaa cacccatcca 360
gaatgtcatt ctacatgagc atcacatttt ccttggtgcc actaactaca tttatgtttt 420
aaatgaggaa gaccttcaga aggttgctga gtacaagact gggcctgtgc tggaacaccc 480
agattgtttc ccatgtcagg actgcagcag caaagccaat ttatcaggag gtgtttggaa 540
agataacatc aacatggctc tagttgtcga cacctactat gatgatcaac tcattagctg 600
tggcagcgtc aacagaggga cctgccagcg acatgtcttt ccccacaatc atactgctga 660
catacagtcg gaggttcact gcatattctc cccacagata gaagagccca gccagtgtcc 720
tgactgtgtg gtgagcgccc tgggagccaa agtcctttca tctgtaaagg accggttcat 780
caacttcttt gtaggcaata ccataaattc ttcttatttc ccagatcatc cattgcattc 840
gatatcagtg agaaggctaa aggaaacgaa agatggtttt atgtttttga cggaccagtc 900
ctacattgat gttttacctg agttcagaga ttcttacccc attaagtatg tccatgcctt 960
tgaaagcaac aattttattt acttcttgac ggtccaaagg gaaactctag atgctcagac 1020
ttttcacaca agaataatca ggttctgttc cataaactct ggattgcatt cctacatgga 1080
aatgcctctg gagtgtattc tcacagaaaa gagaaaaaag agatccacaa agaaggaagt 1140
gtttaatata cttcaggctg cgtatgtcag caagcctggg gcccagcttg ctagacaaat 1200
aggagccagc ctgaatgatg acattctttt cggggtgttc gcacaaagca agccagattc 1260
tgccgaacca atggatcgat ctgccatgtg tgcattccct atcaaatatg tcaacgactt 1320
cttcaacaag atcgtcaaca aaaacaatgt gagatgtctc cagcattttt acggacccaa 1380
tcatgagcac tgctttaata ggacacttct gagaaattca tcaggctgtg aagcgcgccg 1440
tgatgaatat cgaacagagt ttaccacagc tttgcagcgc gttgacttat tcatgggtca 1500
attcagcgaa gtcctcttaa catctatatc caccttcatt aaaggagacc tcaccatagc 1560
taatcttggg acatcagagg gtcgcttcat gcaggttgtg gtttctcgat caggaccatc 1620
aacccctcat gtgaattttc tcctggactc ccatccagtg tctccagaag tgattgtgga 1680
gcatacatta aaccaaaatg gctacacact ggttatcact gggaagaaga tcacgaagat 1740
cccattgaat ggcttgggct gcagacattt ccagtcctgc agtcaatgcc tctctgcccc 1800
accctttgtt cagtgtggct ggtgccacga caaatgtgtg cgatcggagg aatgcctgag 1860
cgggacatgg actcaacaga tctgtctgcc tgcaatctac aaggttttcc caaatagtgc 1920
accccttgaa ggagggacaa ggctgaccat atgtggctgg gactttggat ttcggaggaa 1980
taataaattt gatttaaaga aaactagagt tctccttgga aatgagagct gcaccttgac 2040
tttaagtgag agcacgatga atacattgaa atgcacagtt ggtcctgcca tgaataagca 2100
tttcaatatg tccataatta tttcaaatgg ccacgggaca acacaataca gtacattctc 2160
ctatgtggat cctgtaataa caagtatttc gccgaaatac ggtcctatgg ctggtggcac 2220
tttacttact ttaactggaa attacctaaa cagtgggaat tctagacaca tttcaattgg 2280
tggaaaaaca tgtactttaa aaagtgtgtc aaacagtatt cttgaatgtt ataccccagc 2340
ccaaaccatt tcaactgagt ttgctgttaa attgaaaatt gacttagcca accgagagac 2400
aagcatcttc agttaccgtg aagatcccat tgtctatgaa attcatccaa ccaaatcttt 2460
tattagtggt gggagcacaa taacaggtgt tgggaaaaac ctgaattcag ttagtgtccc 2520
gagaatggtc ataaatgtgc atgaagcagg aaggaacttt acagtggcat gtcaacatcg 2580
ctctaattca gagataatct gttgtaccac tccttccctg caacagctga atctgcaact 2640
ccccctgaaa accaaagcct ttttcatgtt agatgggatc ctttccaaat actttgatct 2700
catttatgta cataatcctg tgtttaagcc ttttgaaaag ccagtgatga tctcaatggg 2760
caatgaaaat gtactggaaa ttaagggaaa tgatattgac cctgaagcag ttaaaggtga 2820
agtgttaaaa gttggaaata agagctgtga gaatatacac ttacattctg aagccgtttt 2880
atgcacggtc cccaatgacc tgctgaaatt gaacagcgag ctaaatatag agtggaagca 2940
agcaatttct tcaaccgtcc ttggaaaagt aatagttcaa ccagatcaga atttcacagg 3000
attgattgct ggtgttgtct caatatcaac agcactgtta ttactacttg ggtttttcct 3060
gtggctgaaa aagagaaagc aaattaaaga tctgggcagt gaattagttc gctacgatgc 3120
aagagtacac actcctcatt tggataggct tgtaagtgcc cgaagtgtaa gcccaactac 3180
agaaatggtt tcaaatgaat ctgtagacta ccgagctact tttccagaag atcagtttcc 3240
taattcatct cagaacggtt catgccgaca agtgcagtat cctctgacag acatgtcccc 3300
catcctaact agtggggact ctgatatatc cagtccatta ctgcaaaata ctgtccacat 3360
tgacctcagt gctctaaatc cagagctggt ccaggcagtg cagcatgtag tgattgggcc 3420
cagtagcctg attgtgcatt tcaatgaagt cataggaaga gggcattttg gttgtgtata 3480
tcatgggact ttgttggaca atgatggcaa gaaaattcac tgtgctgtga aatccttgaa 3540
cagaatcact gacataggag aagtttccca atttctgacc gagggaatca tcatgaaaga 3600
ttttagtcat cccaatgtcc tctcgctcct gggaatctgc ctgcgaagtg aagggtctcc 3660
gctggtggtc ctaccataca tgaaacatgg agatcttcga aatttcattc gaaatgagac 3720
tcataatcca actgtaaaag atcttattgg ctttggtctt caagtagcca aaggcatgaa 3780
atatcttgca agcaaaaagt ttgtccacag agacttggct gcaagaaact gtatgctgga 3840
tgaaaaattc acagtcaagg ttgctgattt tggtcttgcc agagacatgt atgataaaga 3900
atactatagt gtacacaaca aaacaggtgc aaagctgcca gtgaagtgga tggctttgga 3960
aagtctgcaa actcaaaagt ttaccaccaa gtcagatgtg tggtcctttg gcgtgctcct 4020
ctgggagctg atgacaagag gagccccacc ttatcctgac gtaaacacct ttgatataac 4080
tgtttacttg ttgcaaggga gaagactcct acaacccgaa tactgcccag accccttata 4140
tgaagtaatg ctaaaatgct ggcaccctaa agccgaaatg cgcccatcct tttctgaact 4200
ggtgtcccgg atatcagcga tcttctctac tttcattggg gagcactatg tccatgtgaa 4260
cgctacttat gtgaacgtaa aatgtgtcgc tccgtatcct tctctgttgt catcagaaga 4320
taacgctgat gatgaggtgg acacacgacc agcctccttc tgggagacat catagtgcta 4380
gtactatgtc aaagcaacag tccacacttt gtccaatggt tttttcactg cctgaccttt 4440
aaaaggccat cgatattctt tgctcttgcc aaaattgcac tattatagga cttgtattgt 4500
tatttaaatt actggattct aaggaatttc ttatctgaca gagcatcaga accagaggct 4560
tggtcccaca ggccacggac caatggcctg cagccgtgac aacactcctg tcatattgga 4620
gtccaaaact tgaattctgg gttgaatttt ttaaaaatca ggtaccactt gatttcatat 4680
gggaaattga agcaggaaat attgagggct tcttgatcac agaaaactca gaagagatag 4740
taatgctcag gacaggagcg gcagccccag aacaggccac tcatttagaa ttctagtgtt 4800
tcaaaacact tttgtgtgtt gtatggtcaa taacattttt cattactgat ggtgtcattc 4860
acccattagg taaacattcc cttttaaatg tttgtttgtt ttttgagaca ggatctcact 4920
ctgttgccag ggctgtagtg cagtggtgtg atcatagctc actgcaacct ccacctccca 4980
ggctcaagcc tcccgaatag ctgggactac aggcgcacac caccatcccc ggctaatttt 5040
tgtatttttt gtagagacgg ggttttgcca tgttgccaag gctggtttca aactcctgga 5100
ctcaagaaat ccacccacct cagcctccca aagtgctagg attacaggca tgagccactg 5160
cgcccagccc ttataaattt ttgtatagac attcctttgg ttggaagaat atttataggc 5220
aatacagtca aagtttcaaa atagcatcac acaaaacatg tttataaatg aacaggatgt 5280
aatgtacata gatgacatta agaaaatttg tatgaaataa tttagtcatc atgaaatatt 5340
tagttgtcat ataaaaaccc actgtttgag aatgatgcta ctctgatcta atgaatgtga 5400
acatgtagat gttttgtgtg tattttttta aatgaaaact caaaataaga caagtaattt 5460
gttgataaat atttttaaag ataactcagc atgtttgtaa agcaggatac attttactaa 5520
aaggttcatt ggttccaatc acagctcata ggtagagcaa agaaagggtg gatggattga 5580
aaagattagc ctctgtctcg gtggcaggtt cccacctcgc aagcaattgg aaacaaaact 5640
tttggggagt tttattttgc attagggtgt gttttatgtt aagcaaaaca tactttagaa 5700
acaaatgaaa aaggcaattg aaaatcccag ctatttcacc tagatggaat agccaccctg 5760
agcagaactt tgtgatgctt cattctgtgg aattttgtgc ttgctactgt atagtgcatg 5820
tggtgtaggt tactctaact ggttttgtcg acgtaaacat ttaaagtgtt atatttttta 5880
taaaaatgtt tatttttaat gatatgagaa aaattttgtt aggccacaaa aacactgcac 5940
tgtgaacatt ttagaaaagg tatgtcagac tgggattaat gacagcatga ttttcaatga 6000
ctgtaaattg cgataaggaa atgtactgat tgccaataca ccccaccctc attacatcat 6060
caggacttga agccaagggt taacccagca agctacaaag agggtgtgtc acactgaaac 6120
tcaatagttg agtttggctg ttgttgcagg aaaatgatta taactaaaag ctctctgata 6180
gtgcagagac ttaccagaag acacaaggaa ttgtactgaa gagctattac aatccaaata 6240
ttgccgtttc ataaatgtaa taagtaatac taattcacag agtattgtaa atggtggatg 6300
acaaaagaaa atctgctctg tggaaagaaa gaactgtctc taccagggtc aagagcatga 6360
acgcatcaat agaaagaact cggggaaaca tcccatcaac aggactacac acttgtatat 6420
acattcttga gaacactgca atgtgaaaat cacgtttgct atttataaac ttgtccttag 6480
attaatgtgt ctggacagat tgtgggagta agtgattctt ctaagaatta gatacttgtc 6540
actgcctata cctgcagctg aactgaatgg tacttcgtat gttaatagtt gttctgataa 6600
atcatgcaat taaagtaaag tgatgcaaca tcttgtaaaa aaaaaaaaaa aaaaaa 6656
Claims (7)
1.突变的MET基因,其与SEQ ID NO:1的差异在于1个非沉默突变,并且所述突变的MET基因编码与野生型MET蛋白相比,功能异常的蛋白,或导致远端关节弯曲病的发生;
所述非沉默突变是:c.3701A→G。
2.一种载体,其包含权利要求1的突变的MET基因。
3.一种宿主细胞,其包含权利要求1的突变的MET基因或权利要求2的载体。
4.权利要求1的突变的MET基因或权利要求2的载体或权利要求3的宿主细胞的用途,其用于产生远端关节弯曲病动物模型,或用于制备试剂盒,所述试剂盒用于产生远端关节弯曲病动物模型。
5.能够特异性扩增MET基因的第19个外显子的引物在制备诊断剂中的用途,所述诊断剂用于诊断远端关节弯曲病。
6.根据权利要求5所述的用途,其特征在于,所述引物是如SEQ ID NO:2和3所示的引物对。
7.能够特异性扩增MET基因的第19个外显子的引物在制备用于诊断远端关节弯曲病的试剂盒中的用途。
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Cinzia Cristiani等.Regulation of the Wild-type and Y1235D mutant Met kinase activation.《BioChemistry》.2005,14110-14119. * |
NM_000245.3;Li Y et al;《Genbank》;20171228;全文 * |
Regulation of the Wild-type and Y1235D mutant Met kinase activation;Cinzia Cristiani等;《BioChemistry》;20050410;14110-14119 * |
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