Notch3 Mutations in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a Mendelian Condition Causing Stroke and Vascular Dementia

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.

Features of alagille syndrome in 92 patients: Frequency and relation to prognosis

“…10 At present, four human Notch genes and two Jagged genes have been described, but diseases associated with defects in these genes have only been assigned to three of these. 8,27,50 There is an enormous variability of the clinical expression of AGS. It is clear that family members of affected individuals with AGS have minor forms of the syndrome, some of which do not meet diagnostic criteria.…”

“…Mutations in the gene for the Notch 3 receptor cause adult-onset CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), which is associated with intracranial bleeding. 27,28 Patients with CADASIL have small deep cerebral infarcts, leukoencephalopathy, and a nonatherosclerotic, nonamyloid angiopathy involving the media of small cerebral arteries. This strongly implicates abnormalities in the Notch pathway as a cause of CNS vascular pathology.…”

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…Most mutations occur in codons of exon 4, followed by exons 3, 5, 6 and 11 7,9,10 ( Fig 1B). The exon 3 seems to be the second most commonly affected site in French, English and German families 7,9 ; exon 11 could, however, be the second most prevalent in Dutch families 11 . The Notch proteins constitute a family of surface receptors that promote transduction of signals between neighboring cells.…”

“…It consists of 33 exons (23 extracellular) 5,7,8 ( Fig 1A). All mutations occur in extracellular domains, more specifically the epidermal growth-like factor-repeats (EGF-repeats), from a non-paired cysteine 4,7 . Most mutations occur in codons of exon 4, followed by exons 3, 5, 6 and 11 7,9,10 ( Fig 1B).…”

“…All mutations occur in extracellular domains, more specifically the epidermal growth-like factor-repeats (EGF-repeats), from a non-paired cysteine 4,7 . Most mutations occur in codons of exon 4, followed by exons 3, 5, 6 and 11 7,9,10 ( Fig 1B). The exon 3 seems to be the second most commonly affected site in French, English and German families 7,9 ; exon 11 could, however, be the second most prevalent in Dutch families 11 .…”