Genetic study of familial vascular leukoencephalopathy

Notch 3基因位于染色体l9p13.1，最近被鉴定为常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（CADASIL）的致病基因。为了研究Notch突变对家族性血管性白质脑病的遗传贡献，我们筛选了来自11个无亲缘关系的家族中的13名具有CADASIL样症状和阳性家族史的患者，并在来自4个家族的5名患者中鉴定了3种不同的错义突变。其中两个（Arg 9 Ocys和Arg 133 Cys）与之前在白人患者中报道的相同，另一个（Cysl 74 Phe）是一种新型突变，导致Notch 3细胞外表皮生长因子（EGF）样重复序列中半胱氨酸的缺失。这些数据表明Notch 3基因与不同种族的CADASIL患者有关，其突变频率在家族性白质脑病中约为35%。然而，也有家族中没有发现Notch 3突变，这表明基因座和/或等位基因异质性。

The Notch3 gene, located on chromosome l9p13.1, have been recently identified as a causative gene for Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). To investigate the genetic contribution of Notch mutations to familial vascular leukoencephalopathy, we screened 13 patients from 11 unrelated families with CADASIL-like symptoms and positive family history and identified three different missense mutations in five patients from 4 families. Two of which (Arg9Ocys and Argl33Cys) were the same as previously reported in Caucasian patients, the other (Cysl74Phe) was a novel mutation caused a loss of a cysteine in extracellular epidermal growth factor (EGF)-like repeats of Notch3. These data indicate that Notch3 gene is responsible for CADASIL patients in different ethnic groups, and its mutation frequency is approximately 35 % in familial leukoencephalopathy. However, there were also families in which no mutations in Notch3 were found, which indicates locus and /or allelic heterogeneity.