伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病四个家系的NOTCH3基因突变研究

NOTCH3 gene mutations in four Chinese families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

目的 报告 4个伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL)家系的NOTCH3基因突变特点。方法 对 4个经临床和病理检查证实的CADASIL家系中的先证者作NOTCH3基因编码区外显子 1～ 12的聚合酶链反应 (PCR)和DNA测序 ,对家系 2和 4中的部分亲属也作了同样的检查。结果 4个家系中的先证者均发现有NOTCH3基因的杂合性错义突变 ,先证者 1为外显子 3的 2 6 8C→T突变 ,先证者 2为外显子 3的 32 2C→T突变 ,先证者 3为外显子 3的 32 8C→T突变 ,先证者 4为外显子 11的 1819C→T突变 ,分别造成Notch3蛋白质R90C、C10 8R、R110C和R6 0 7C 4个位点氨基酸的替换。其中先证者 2的C10 8R突变尚未见文献报道。在家系 2和家系 4中 ,部分成员也携带与先证者同样的突变。结论 这 4个家系的CADASIL病均由NOTCH3基因的突变引起 。

Objectives To search for mutations in NOTCH3 gene in four Chinese families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods Four probands from four unrelated families with typical manifestations of CADASIL were studied The 1～12 coding exons and their flanking intron sequences of NOTCH3 gene were amplified by PCR and sequenced Some family members in the pedigree 2 and 4 were also examined for the NOTCH3 gene mutations Results Four heterozygous missense mutations were identified in the four families: the proband 1 carrying a 268C→T mutation in exon 3, the proband 2 a 322 C→T mutation in exon 3,the proband 3 a 328 C→T mutation inexon 3,and the proband 4 a 1819 C→T mutation in exon 11, which resulted in the amino acid substitutions of R90C, C108R, R110C, and R607C respectively Among them the C108R is a novel mutation not reported previously Additionally, some members in the pedigree 2 and 4 also harbored the same mutations with the probands Conclusion Four heterozygous missense mutations in NOTCH3 gene have been found in four Chinese families with CADASIL Different point mutations in NOTCH3 lead to similar phenotype of the disease To search for mutations in NOTCH3 in related patients will help further understand and accurately diagnose the disease and perform prenatal diagnosis in CADASIL families