一个结节性硬化症家系致病基因新突变鉴定

A novel mutation identified in a family with tuberous sclerosis complex

目的结节性硬化症(TSC)是一种累及多系统的常染色体显性遗传病,以全身多种组织器官出现错构瘤样增生为主要特征,其致病基因为TSC1和TSC2基因,本研究旨在对一中国汉族结节性硬化症家系进行基因突变分析,以明确临床诊断并指导遗传咨询。方法设计PCR引物,扩增TSC1和TSC2外显子及外显子-内含子交界区并进行Sanger测序和片段克隆测序分析,确定突变位点并探讨突变致病的可能机制。结果 TSC1基因测序分析发现先证者第15外显子存在两个杂合突变,c.1556C>T和c.1888_1891del AAAG。克隆测序结果显示,先证者的两个突变均来自于同一个等位基因。第一个突变可能影响TSC1与粘着斑激酶家族作用蛋白FIP200的结合,第二个突变形成了提前的终止密码,推测可能形成截短的蛋白分子,或者通过无义介导的m RNA降解机制被降解而致病。结论TSC1基因c.1556C>T和c.1888_1891del AAAG为结节性硬化症家系致病突变,对患者明确诊断及遗传咨询有重要意义。

Objective uberous sclerosis complex（TSC）is an autosomal dominant genetic disease involving multiple systems,characterized by hamartoma hyperplasia in a variety of tissues and organs.TSC is caused by the mutation in TSC1 or TSC2.This study aimed to detect gene mutations in a Chinese Han TSC family,establish definitive diagnosis and provide genetic counseling.Methods The PCR primers covering all the TSC1 and TSC2 exons and exon-intron boundaries were designed,then Sanger sequencing and cloning sequencing analysis were performed to explore pathogenic mechanism of the mutation.Results We found two heterozygous mutations in exon 15 of TSC1,c.1556C〉T and c.1888_1891del AAAG;two mutations are from the same allele,the first mutation may affect interaction between TSC1 and focal adhesion kinase[FAK] family interacting protein of 200 k D（FIP200）,the second mutation resulted in a premature stop codon that may form a truncated TSC1 m RNA molecule,or degraded by nonsense mediated m RNA degradation.Conclusion TTSC1 gene c.1556C〉 T and c.1888_1891del AAAG are pathogenic mutations for the TSC family,which is of great significance to patient＇s diagnosis and genetic counseling.