NOTCH3 MUTATIONS IN CADASIL, A HEREDITARY ADULT-ONSET CONDITION CAUSING STROKE AND DEMENTIA

STROKE is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cereb ral autosomal dominant arteriopathy with subcortical infarcts and leuk oencephalopathy) causes a type of stroke and dementia whose key featur es include recurrent subcortical ischaemic events and vascular dementi a and which is associated with diffuse white-matter abnormalities on n euroimaging(1,2). Pathological examination reveals multiple small, dee p cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries(3 ). Severe alterations of vascular smooth-muscle cells are evident on u ltrastructural analysis(4). We have previously mapped the mutant gene to chromosome 19 (ref. 5). Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We h ave identified mutations in CADASIL patients that cause serious disrup tion of this gene, indicating that Notch3 could be the defective prote in in CADASIL patients.