伴皮质下梗死及白质脑病常染色体显性遗传性脑动脉病的NOTCH3基因诊断  

NOTCH3 gene diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

作　　者：唐晓梅[1] 杨静芳[1] 冯秀丽[1] 牛小媛[2] 李阳[2] 陈秀云[3] 陈彪[1] 

机构地区：[1]首都医科大学宣武医院老年病研究所,北京北京海淀医院神经内科100053 [2]山西医科大学附属医院神经内科 [3]温州医学院附属医院神经内科

出　　处：《临床神经病学杂志》2008年第3期164-167,共4页Journal of Clinical Neurology

基　　金：国家863计划"脑卒中遗传资源中心库及收集网络的建立"(2001AA227051)

摘　　要：目的分析伴皮质下梗死及白质脑病常染色体显性遗传性脑动脉病(CADASIL)的NOTCH3基因突变类型。方法对临床诊断为CADASIL的4例先证者、来自3个家系10例患者及4例无类似临床表现成员、以及100名健康对照者进行NOTCH3基因PCR扩增及变性高压液相色谱分析(DHPLC)检测;对DH-PLC阳性结果进行DNA双向测序,明确致病性突变或多态类型。结果在CADASIL先证者及其家系患者中共发现134半胱氨酸→酪氨酸(Cys134Tyr)、141精氨酸→半胱氨酸(Arg141Cys)、90精氨酸→半胱氨酸(Arg90Cys)3种突变类型,存在于第3、第4外显子,为杂合错义突变。同时发现15种多态类型。其中家系1和家系2中分别发现1名成员与先证者存在相同位点的NOTCH3基因致病性突变,尚未出现与先证者相应的临床表现,被确定为临床前期患者。结论NOTCH3单基因突变是CADASIL的分子遗传学基础,第3、4外显子可能是中国CADASIL家系的热点突变区。第4外显子Cys134Tyr突变类型为国内首次报告。Objective To analyse the mutation types of the NOTCH3 gene with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy （CADASIL）. Methods Including 4 probands of CADASIL,10 cases of CADASIL and 4 normal members from 3 CADASIL families and 100 healthy controls were recruited. Genomic DNA was extracted from white blood cell. The amplieons were analyzed by the denaturing highperformance liquid chromatography （DHPLC） technique. The positive samples which identified by the DHPLC were sequenced to determine the specific mutation or polymorphism, respectively. Results Three heterozygous missense mutations including Cys90Arg, Arg141Cys, Cys134Tyr located in the exon3 and exon4 were found in the 4 probands and 10 cases of CADASIL among the 3 families. 15 polymorphisms were also found. 2 members individual from family 1 and 2 were found to carry the same pathological mutations as in their proband but without clinical symptoms. They were identified as preclinical patients. Conclusions Mutation detection of NOTCH3 is the molecular genetic mechanical for CADASIL. The exon3 and exon4 are possible hot mutation spots in Chinese patients. The mutation of Cys134Tyr in exon4 is a novel mutation which has not been reported previousiy in China.

关 键 词：伴皮质下梗死及白质脑病常染色体显性遗传性脑动脉病 NOTCH3基因 突变 

分 类 号：R749.13[医药卫生—神经病学与精神病学]