Investigation of the Familial Cadasil Gene NOTCH3 in Ischemic Stroke

One approach to mapping 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 disease and Parkinson's disease, have 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 observed in a patient with vascular dementia and an older patient mildly affected by sporadic stroke, and the oldest CADASIL patient identified was 94 years old. The pathomechanism behind NOTCH3 mutations causing ischemic stroke in CADASIL still isn't clearly defined.

Our project on the familial CADASIL gene NOTCH3 in ischemic stroke is exploring the relationship among NOTCH3 genetic variants that we hypothesize to increase susceptibility to ischemic stroke.

Establishing the effects of NOTCH3 variability and exploring this with environmental factors such as smoking may help identify subsets of at-risk individuals and promote preventive 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.