Genetic study of familial vascular leukoencephalopathy

Notch3基因位于染色体l9p13.1上，最近被确定为大脑常染色体显性动脉病变伴皮层下梗死和白质脑病（CADASIL）的致病基因。为了研究Notch突变对家族性血管性脑白质病的遗传贡献，我们从11个具有cadasil样症状和阳性家族史的不相关家族中筛选了13例患者，并在4个家族的5例患者中发现了3种不同的错义突变。其中两种（Arg9Ocys和Argl33Cys）与之前在高加索患者中报道的相同，另一种（Cysl74Phe）是一种新的突变，导致Notch3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，Notch3基因与不同民族的CADASIL患者有关，其在家族性脑白质病中的突变频率约为35%。然而，也有家族未发现Notch3突变，这表明位点和/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.