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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy is the most common monogenic form of ischemic cerebral small-vessel disease. CADASIL is associated with highly stereotypical mutations in the extracellular domain of the Notch 3 receptor. Working in collaboration with the Artavanis-Tsakonas lab we demonstrated that two phenotypically distinct human mutations define different hypomorphic activity states of the receptor and are characterizing transgenic mouse models that parallel remarkably the human condition.