CADASIL: Genetics and pathophysiology

CADASIL, an autosomal dominant adult onset arteriopathy causing stroke and dementia in humans, is underlaid by a non atherosclerotic non amyloid angio pathy involving mainly the media of small cerebral arteries; it is characte rized by major lesions of vascular smooth muscle cells. Using a positional cloning approach, we mapped CADASIL locus on chromosome 19 and identified t he mutated gene as being Notch3. This gene, previously unknown in humans, e ncodes for a large transmembrane receptor belonging to the Notch/lin12 gene family which are known to be involved in cell fate specification during de velopment. Genetic analysis of more than 120 CADASIL unrelated families all owed us to show that these mutations are highly stereotyped and affect only the extra cellular domain of the protein. On the basis of these data, a mo lecular diagnostic test has been set up and is now widely required by clini cians involved in the diagnosis of vascular leukoencephalopathies. Using th is test, we recently showed that CADASIL can also occur in patients who do not have any affected relative due to the existence of notch3 de novo mutat ions. As a first step to investigate the molecular and cellular mechanisms leading from Notch3 mutations to CADASIL phenotype, we analyzed by in-situ hybridization and immunohistochemistry the pattern of expression of this ge ne. Notch3 expression is highly restricted to the vascular smooth muscle ce ll in normal human adults. In CADASIL tissues there is a dramatic accumulat ion of the extracellular domain of the protein which suggests that one of t he main mechanisms of CADASIL involves anomalies in the proteolytical cleav age and clearance of this protein. These data provide important clues to th e mechanisms of this condition mid current work should lead in the next fut ure to a complete understanding of CADASIL and set up the basis of a ration al therapeutical approach of this condition.