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CADASIL: Notch signaling defect or protein accumulation problem?

Nancy B. Spinner
J Clin Invest. 2000;105(5):561-562. https://doi.org/10.1172/JCI9511.
When studies of the genetic etiology of human disease intersect with those of basic mechanisms in developmental biology, our understanding of normal and abnormal development is increased, and the knowledge gained enriches the work of both human geneticists and basic scientists. Such is the case with the work of A. Joutel et al. (1), who have previously demonstrated that mutations in the Notch3 gene are the cause of the autosomal dominant disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL is an adult-onset neurologic disorder (average age of onset is 45 years) characterized by recurrent strokes and dementia. Through positional cloning, Notch3 was found to be the gene responsible for the disorder (1), and mutations have been demonstrated in more than 90% of CADASIL patients (1, 2). The highly conserved Notch signaling pathway was originally identified and studied in the fruit fly Drosophila melanogaster. The name “Notch” derives from the characteristic notched wing found in flies carrying only 1 functioning copy of the gene. Homozygous Notch mutations are lethal, and affected embyros have severe abnormalities, including an excess of neural cells (3). A large body of work in the fruit fly, the nematode Caenorhabditis elegans, and more recently in vertebrates has revealed that this pathway plays a prominent role in development by contributing to the determination of […]

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