CN114015768A - 检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征试剂盒中的应用 - Google Patents
检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征试剂盒中的应用 Download PDFInfo
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Abstract
本发明涉及检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用,属于诊断试剂技术领域。本发明通过进行基因检测可及时对患者作出明确诊断,改变马凡综合征患者治疗策略,并有助于确定可能受累的家庭成员,改变患者的随访频率。本发明受基金项目:国家自然科学基金项目(81974042);临床与转化医学研究基金项目(2019‑F31‑LC)资助。
Description
技术领域
本发明涉及诊断试剂技术领域,具体涉及检测FBN1基因突变位点 c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用。
背景技术
马凡综合征(Marfan syndrome,MFS)是一种遗传性结缔组织病,最常见的遗传方式为常染色体显性遗传。MFS的临床表现轻重不一,部分患者仅表现出MFS的单一特征,而部分病情较重的患者在新生儿期即出现累及多个器官系统的严重且快速进展的病变。
马凡综合征的累及范围包括眼部、心血管、肌肉骨骼、肺部、皮肤和中枢神经系统。主动脉根部疾病是MFS患者出现并发症和死亡的主要原因。它会引起动脉瘤样扩张、主动脉瓣关闭不全和主动脉夹层,严重者可出现主动脉瘤破裂,造成患者死亡。在心脏结构病变方面,MFS患者常伴有二尖瓣脱垂,如未及时处理则可导致心力衰竭的发生。MFS个体还存在过度的长骨线性生长和关节松弛,且50%~80%的MFS患者存在晶状体异位。
目前已知的与MFS发病相关的基因主要为FBN1及TGFBR。FBN1位于第15号染色体,含65个外显子,负责编码原纤维蛋白-1蛋白。原纤维蛋白-1是弹性组织和非弹性组织的一种重要基质成分,是细胞外微原纤维的主要构成蛋白。而细胞外微原纤维则促进了弹力纤维的形成和维持。
自20余年前首次报告FBN1基因的突变可导致MFS以来,FBN1通用突变数据库已登记了1800余种与该蛋白质相关的不同突变。作为一种常染色体遗传病,诊疗机构可通过已知的突变位点设计试剂盒对可疑患者进行测序及比对,从而明确患者诊断,修正治疗方案。但目前MFS的突变数据库仍不完善。
发明内容
本发明的目的在于提供检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用。本发明本发明通过进行基因检测可及时对患者作出明确诊断,改变马凡综合征患者治疗策略,并有助于确定可能受累的家庭成员,改变患者的随访频率。
本发明提供了检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用。
优选的是,所述突变位点在FBN1基因第32外显子上。
本发明还提供了一种诊断马凡综合征的引物,所述引物的核苷酸序列如 SEQ IDNO.1~2所示。
本发明还提供了一种诊断马凡综合征的试剂盒,所述试剂盒包括上述技术方案所述的引物和反应试剂。
本发明还提供了一种马凡综合征相关突变基因,所述基因在FBN1基因的基础上进行以下突变得到:c.G3901T:编码区第3901位碱基G突变成T。
本发明提供了检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用。本发明通过对一个马凡综合征家系进行二代全外显子测序及一代测序验证,首次确定了该家系成员第15号染色体FBN1 基因的第32外显子上存在突变位点c.G3901T。经验证,该错义突变可导致 FBN1基因第1301个氨基酸由甘氨酸转变为半胱氨酸,从而使FBN1蛋白的结构和功能受到破坏,导致马凡综合征。通过采集受检者外周血,提取基因组DNA,针对包含位点的FBN1基因片段设计上下游引物,并进行Sanger 测序,以检测受检者的FBN1基因是否存在c.G3901T突变,即可辅助马凡综合征的快速诊断;本发明在既往研究的基础上首次报道了FBN1基因上一个新的突变位点,补充了MFS的突变数据库,完善了MFS诊断的突变基因谱,提高MFS的检出率,进一步提高了基因检测的水平;本发明通过进行基因检测可及时对患者作出明确诊断,改变马凡综合征患者治疗策略,并有助于确定可能受累的家庭成员,改变患者的随访频率;本发明还提供了一种诊断马凡综合征的试剂盒,可用于产前胎儿马凡综合征早期诊断,患病家系可通过此试剂盒在早期对胎儿进行马凡综合征的筛查,减少从源头减少马凡综合征的发生。
附图说明
图1为本发明提供的Sanger测序提示马凡综合征FBN1基因c.G3901T 位点突变结果图。
具体实施方式
本发明提供了检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用。本发明发现了一个FBN1基因突变的马凡综合征家系,经过二代全外显子测序及一代测序验证,本发明首次确定了该家系成员第15号染色体FBN1基因(转录本版本号:NM_000138.5)的第32外显子上存在突变位点c.G3901T。经过生物信息学分析确定了FBN1基因上错义突变c.G3901T为马凡综合征新的致病突变;此后通过对家系中其它成员进行Sanger测序,确定该位点为遗传突变位点。经验证,该错义突变导致可导致FBN1基因第1301个氨基酸由甘氨酸转变为半胱氨酸,从而使FBN1 蛋白的结构和功能受到破坏,导致马凡综合征。
本发明还提供了一种诊断马凡综合征的引物,所述引物的核苷酸序列如 SEQ IDNO.1~2所示:
上游引物:5’-CATTGTTTTTCTGAGGGAAAGC-3’(SEQ ID NO.1);
下游引物:5’-CACACCTGTACAGCCAGTTTTT-3’(SEQ ID NO.2)。
本发明通过采集受检者外周血,提取基因组DNA,针对包含突变位点的FBN1基因片段设计上下游引物,并进行Sanger测序,以检测受检者的 FBN1基因是否存在c.G3901T突变,辅助马凡综合征的快速诊断。
本发明还提供了一种诊断马凡综合征的试剂盒,所述试剂盒包括上述技术方案所述的引物和反应试剂。
本发明还提供了一种马凡综合征相关突变基因,所述基因在FBN1基因的基础上进行以下突变得到:c.G3901T:编码区第3901位碱基G突变成T。本发明所述基因能够作为一种新的马凡综合征诊断标志物,可应用于马凡综合征诊断试剂盒的制备,本发明所述基因作为诊断标志物为带有突变位点 c.G3901T的FBN1基因片段。
下面结合具体实施例对本发明所述的检测FBN1基因突变位点 c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用做进一步详细的介绍,本发明的技术方案包括但不限于以下实施例。
实施例1
本研究得到了中国医学科学院阜外医院伦理委员会的批准。所有参与者均自愿参加并签署了知情同意书。患者的辅助检查及马凡综合征诊断由中国医学科学院阜外医院完成。
分别采集每位研究对象(先证者)4ml外周静脉血并进行全外显子测序:使用DNA试剂盒提取全血DNA,评估DNA降解程度。随后,将基因组DNA 打成短片段,并对片段末端进行修饰。加工完成的文库使用核酸片段筛选试剂盒完成有效序列的筛选,然后经PCR扩增后与生物素标记的探针进行液相杂交,再使用链霉素亲和磁珠捕获基因中的外显子。经纯化及PCR扩增后的DNA文库进行定量。质检合格的样本在Illumina平台进行高通量测序。
在获得原始测序序列后,将原始测序序列与参考基因组(GRCh37/hg19) 进行比对。随后使用软件对SNP、InDel和CNV进行注释。通过千人基因组项目数据库(1000g_all)、ESP6500数据库(esp6500siv2_all)、gnomAD数据库(gnomAD_ALL和gnomAD_EAS)进行筛选。最后根据该疾病在家系中的遗传模式,筛选候选基因,随后进行GO/KEGG富集分析,并使用genemania软件GeneMania对候选基因进行蛋白功能互作网络分析,列出候选基因排序。
根据全外显子测序及生物信息学分析结果,首次确定了该家系成员第15 号染色体FBN1基因的第32外显子上存在突变位点c.G3901T(p.G1301C)。经验证,该错义突变导致可导致FBN1基因第1301个氨基酸由甘氨酸转变为半胱氨酸,从而使FBN1蛋白的结构和功能受到破坏,导致马凡综合征。
确定致病突变位点后,设计正反向引物,收集家系成员外周静脉血,进行PCR扩增及电泳、产物纯化及上机测序,完成家系成员的一代Sanger测序验证。
在上述马凡综合征诊断试剂盒中,所述的特异性扩增引物为:
上游引物:5’-CATTGTTTTTCTGAGGGAAAGC-3’(SEQ ID NO.1)
下游引物:5’-CACACCTGTACAGCCAGTTTTT-3’(SEQ ID NO.2)
反应体系如表1所示:
表1反应体系
反应条件如表2所示:
表2反应条件
PCR扩增产物进行Sanger测序(如图1)
由图1可见,箭头所指处出现G向T的杂合突变,经数据库查询该处错义突变导致甘氨酸转变为半胱氨酸,从而影响蛋白质结构和功能,导致马凡综合征的发生。
经验证,先证者的患病女儿也参与了测序并检测出了相同的突变位点,说明本发明能够有效实现马凡综合征疾病的诊断。
现有检测试剂盒不包含有本发明所描述的突变位点。与现有技术相比,本发明进一步解决了:
①通过对马凡综合征患者进行全外显子测序,首次发现了第15号染色体FBN1基因的第32外显子上存在突变位点c.G3901T(p.G1301C)。本诊断标记物及诊断试剂盒可通过采集患者及家属外周血,并进行Sanger测序,即可快速检出是否携带有致病突变位点,以协助诊断。
②该位点首次申请专利,补充了马凡综合征的遗传突变谱,实现了马凡综合征的早期诊断。
③该诊断标记物及诊断试剂盒还可以作为马凡综合征妊娠前及妊娠期产前筛检,降低患病婴儿降生率,从源头上降低该病的发病率。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 中国医学科学院阜外医院
<120> 检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征试剂盒中的应用
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
cattgttttt ctgagggaaa gc 22
<210> 2
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
cacacctgta cagccagttt tt 22
Claims (6)
1.检测FBN1基因突变位点c.G3901T的试剂在制备诊断马凡综合征的试剂盒中的应用。
2.根据权利要求1所述的应用,其特征在于,所述突变位点在FBN1基因第32外显子上。
3.一种诊断马凡综合征的引物,其特征在于,所述引物的核苷酸序列如SEQ ID NO.1~2所示。
4.一种诊断马凡综合征的试剂盒,其特征在于,所述试剂盒包括权利要求3所述的引物和反应试剂。
6.一种马凡综合征相关突变基因,所述基因在FBN1基因的基础上进行以下突变得到:c.G3901T:编码区第3901位碱基G突变成T。
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