Ungaro C, Mazzei R, Conforti F L, Sprovieri T, Servillo P, Liguori M, Citrigno L, Gabriele A L, Magariello A, Patitucci A, Muglia M, Quattrone A
Institute of Neurological Sciences, National Research Council, Mangone, Italy.
J Neurosci Res. 2009 Apr;87(5):1162-7. doi: 10.1002/jnr.21935.
CADASIL is a cerebrovascular disease caused by mutations in the NOTCH3 gene. Most mutations result in a gain or loss of cysteine residue in one of the 34 epidermal growth factor-like repeats in the extracellular domain of the Notch3 protein, thus sparing the number of cysteine residues. To date, more than 130 different mutations in the NOTCH3 gene have been reported in CADASIL patients, of which 95% are missense point mutations. Many polymorphisms have also been identified in the NOTCH3 coding sequence, some of them leading to amino acid substitutions. The aim of the present study was to analyze the NOTCH3 gene in a large group of patients affected by leukoencephalopathy and to investigate the presence of genetic variants. The molecular analysis revealed several nucleotide alterations. In particular, we identified 20 different mutations, 22 polymorphisms, and 8 genetic variants of unknown pathological significance never reported previously. We hope that this NOTCH3 gene mutational analysis, performed in such a significant number of unrelated and related patients affected by leukoencephalopathy, will help in molecular screening for the NOTCH3 gene, thus contributing to enlargement of the NOTCH3 gene variation database.
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（CADASIL）是一种由NOTCH3基因突变引起的脑血管疾病。大多数突变导致Notch3蛋白细胞外结构域34个表皮生长因子样重复序列之一中半胱氨酸残基的增加或减少，从而保留了半胱氨酸残基的数量。迄今为止，CADASIL患者中已报道了130多种NOTCH3基因的不同突变，其中95%为错义点突变。在NOTCH3编码序列中也发现了许多多态性，其中一些导致氨基酸替换。本研究的目的是分析一大组患有白质脑病患者的NOTCH3基因，并调查基因变异的存在情况。分子分析揭示了几种核苷酸改变。特别是，我们鉴定出20种不同的突变、22种多态性以及8种以前从未报道过的具有未知病理意义的基因变异。我们希望在如此大量患有白质脑病的无关和相关患者中进行的这种NOTCH3基因突变分析，将有助于NOTCH3基因的分子筛查，从而有助于扩大NOTCH3基因变异数据库。
