Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients
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DOI：
10.1016/s0140-6736(97)08083-5
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发表时间：
1997-11-22
期刊：
影响因子：
168.9
通讯作者：
TournierLasserve, E
中科院分区：
文献类型：
--
作者：
Joutel, A;Vahedi, K;TournierLasserve, E
背景CADASIL（伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病）由于其最近的发现和其多变的表现模式而常被忽视或误诊。CADASIL中的缺陷基因是Notch3，其编码大的跨膜受体。方法采用单链构象多态性、异源双链和序列分析方法，对50例无血缘关系的CADASIL患者和100例健康对照者进行Notch3基因沿着全序列的突变筛查，并对其中的100例进行了序列分析。在45例患者中检测到位于Notch3细胞外结构域中的表皮生长因子样（EGF样）重复序列内的突变，观察到编码前五个EGF样重复序列的两个外显子内的突变聚集（32例患者）。所有这些突变导致半胱氨酸残基的丢失或获得，因此导致给定EGF结构域内的半胱氨酸残基的不配对数目。由于在CADASIL患者中检测到的致病性突变的强聚集性和高度定型的性质，CADASIL的简单可靠的诊断测试是可行的。该发现表明，由于与另一个Notch3分子或与另一种蛋白质的异常二硫键桥接，可能参与了这种疾病的发病机制。
Background CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is commonly overlooked or misdiagnosed owing to its recent identification and its variable mode of presentation. The defective gene in CADASIL is Notch3, which encodes a large transmembrane receptor. To set up a diagnostic test and to delineate the Notch3 domains involved in CADASIL, we undertook mutations analysis in this gene in a group of CADASIL patients.Methods 50 unrelated patients with CADASIL and 100 healthy controls were screened for mutations along the entire Notch3 sequence, by means of single-strand conformation polymorphism, heteroduplex, and sequence analysis.Findings Strongly stereotyped mis-sense mutations, located within the epidermal-growth-factor-like (EGF-like) repeats, in the extracellular domain of Notch3, were detected in 45 patients, Clustering of mutations within the two exons encoding the first five EGF-like repeats was observed (32 patients). All these mutations lead to toss or gain of a cysteine residue and therefore to an unpaired number of cysteine residues within a given EGF domain. None of these mutations was found in the 100 controls.Interpretation Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, an easy and reliable diagnostic test for CADASIL is feasible, The findings suggest that aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of this disorder.