汉族家族性中枢神经系统海绵状血管畸形致病基因的一个新突变位点

A novel Krit-1 mutation in Han family with cerebral cavernous malformation

目的 探查汉族家族性中枢神经系统海绵状血管畸形(CCM)的突变基因。方法 选择经神经科确诊的2个家系(A及B)和8例散发性中枢神经系统海绵状血管畸形病例。所有受检对象临床表现有癫痫、突发头痛;2例伴有皮肤病变。候选基因为已确认的Krit-1,对该基因的16个编码外显子进行PCR扩增,扩增产物进行直接测序。结果 受检的A家系在第14外显子的第1289(从起始密码子计算,或2308即从mRNA的第一个碱基计算)位核苷酸一个拷贝有C→G的取代,出现编码改变(S430X),形成终止密码子(UGA),使翻译过程提前终止,导致的基因异常属无义点突变。同法筛查,A家族中有1名成员突变未获得遗传;散发病例发现一个正常多态性变化,未见到突变。结论 发现第1例汉族人CCM基因的点突变,也是国际上未见报道的新位点。这一点突变将会导致一种截短蛋白,是CCM发生的基本原因。研究结果可用于症状前基因诊断。

Objective To detect the mutations of Krit-1 gene that cause familial cerebral cavernous malformation (CCM) in the Han ethnic origin. Methods The subjects were hospitalized in the Department of Neurosurgery, Tiantan Hospital affiliated to Capital University of Medical Sciences. Two families (A and B) and 8 apparently sporadic individuals affected with CCM were screened for mutations of Krit-1 gene. Members of the family CCM have a wide range in age of onset with seizures, headaches and skin lesions. The gene was screened by PCR amplification of 16 exons and mutation was detected by direct sequencing. Results In family A samples, analysis of the Krit-1 gene revealed a new point mutation in exon 14 [ a heterozygous C to G transition at nucleotide 1 289 ( counting from the start codon or nt 2 308 counting from the first nt of the mRNA, aligned according to Gene Bank AF388384) ] which predicts the substitution of a premature termination codon for Serine at codon 430 (S430X) , belonging a nonsense point mutation. No mutation was identified in one of family A members as well as in any of the sporadic individuals with the exception of a single nucleotide polymorphism. Conclusions Report the first family in the Han with CCM having a novel mutation in the CCM1 gene on the continent of Asia. The newly identified mutation creates a premature termination codon and is predicted to produce a truncated Krevl interaction-trapped 1 protein, KRIT1. This result allows efficient presymptomatic molecular diagnosis.