A novel cysteine-sparing G73A mutation of NOTCH3 in a Chinese CADASIL family.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic disease leading to stroke and vascular dementia. CADASIL is an inherited small blood vessel disease caused by mutations in the gene encoding the neurogenic locus notch homolog protein 3 (NOTCH3). NOTCH3 is large type I membrane receptor mainly expressed in vascular smooth muscle cells and pericytes. Most identified mutations result in insert or deletion of a cysteine residue within the EGF-like repeats. To date, some cases with a cysteine-sparing mutant have been described. Genetic analysis revealed a novel mutation in NOTCH3 in a CADASIL family. Molecular analysis revealed its potential pathogenic mechanism in causing CADASIL. In this paper, we present a Chinese family with a novel cysteine-sparing mutation in exon 3 (c.218G>C, p.G73A) of the NOTCH3 gene. Family carriers of the same mutation presented with symptoms and imaging abnormalities characteristic of CADASIL. The location of glycine 73 in between C5-C6 disulfide bond of EGF-like domain 1 shows high conservation from humans to zebra fish. It has previously been suggested that the aggregate-prone property of mutant NOTCH3 contributes to a cytotoxic effect in the pathogenic mechanism underlying CADASIL. Here, we investigated the pathogenic mechanism of the new mutation in vitro using HEK293 cells transfected with either a wild-type (WT) or c.218G>C (p.G73A) NOTCH3