Investigation of the Familial Cadasil Gene NOTCH3 in Ischemic Stroke

Granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL).

Granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL). Magnification of GOM shows electron-dense material surrounded by amorphous finely granular material adjacent to the plasma membrane of a smooth muscle cell (original magnification × 60,000).

One approach to the mapping of stroke-related genes has been the identification of rare Mendelian forms. The classical linkage method employing large familial aggregates that display patterns of stroke inheritance (dominant/recessive) has identified genes involved in monogenic forms of disease. Pathogenic mutations in the NOTCH3 gene [OMIM*600276] are observed to result in cerebral autosomal-dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL; OMIM #125310) a form of small-vessel occlusive disease. Lessons from other disorders, such as Alzheimer’s and Parkinson’s disease, has demonstrated that often the sporadic forms of disease may be influenced by less penetrant pathogenic genetic variation in the familial genes. Interestingly, NOTCH3 mutations have been recently observed in both a vascular dementia patient, a mildly affected sporadic octogenarian stroke patient and the eldest CADASIL patient identified was 94 years of age. The pathomechanism behind NOTCH3 mutations causing ischemic stroke in CADASIL is still not clearly defined. This project will explore the relationship between NOTCH3 genetic variants which we hypothesize to increase susceptibility to ischemic stroke. Establishing the effects of NOTCH3 variability and exploring this with environmental factors such as smoking will help identify subsets of at-risk individuals, and promote preventative diagnosis and treatment. The genetic variants influencing stroke susceptibility may also be the driving force behind the generation of both in vitro and in vivo model systems which will allow safety and efficacy profiling in the development of targeted therapeutics.