New findings from INSERM in the area of genetics & genomics published
2007 JUN 26 -- A new study, "The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo," is now available. "Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy (CADASIL) is the most prominent known cause of inherited stroke and vascular dementia in human adult. The disease gene, NOTCH3, encodes a transmembrane receptor primarily expressed in arterial smooth muscle cells (SMC)," scientists in Paris, France report. "Pathogenic mutations lead to an odd number of cysteine residues within the NOTCH3 extracellular domain (NOTCH3(ECD)), and are associated with progressive accumulation of NOTCH3(ECD) at the SMC plasma membrane. The murine homolog, Notch3, is dispensable for viability but required post-natally for the elaboration and maintenance of arteries. How CADASIL-associated mutations impact NOTCH3 function remains a fundamental, yet unresolved issue. Particularly, whether NOTCH3(ECD) accumulation may titrate the ligand and inhibit the normal pathway is unknown. Herein, using genetic analyses in the mouse, we assessed the functional significance of an archetypal CADASIL-associated mutation (R90C), in vivo, in brain arteries. We show that transgenic mouse lines expressing either the wild-type human NOTCH3 or the mutant R90C human NOTCH3, at comparable and physiological levels, can rescue the arterial defects of Notch3-/-mice to similar degrees. In vivo assessment of NOTCH3/RBP-Jk activity provides evidence that the mutant NOTCH3 protein exhibits normal level of activity in brain arteries. Remarkably, the mutant NOTCH3 protein remains functional and does not exhibit dominant negative interfering activity, even when NOTCH3(ECD) accumulates," wrote M. Monet and colleagues, INSERM. The researchers concluded: "Collectively, these data suggest a model that invokes novel pathogenic roles for the mutant NOTCH3 protein rather than compromised NOTCH3 function as the primary determinant of the CADASIL arteriopathy." Monet and colleagues published their study in Human Molecular Genetics (The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo. Human Molecular Genetics, 2007;16(8):982-92). For more information, contact M. Monet, INSERM U740, Paris F-75010, France. Publisher contact information for the journal Human Molecular Genetics is: Oxford University Press, Great Clarendon St., Oxford OX2 6DP, England. Keywords: France, Paris, Genetics & Genomics, Genetics. This article was prepared by Life Science Weekly editors from staff and other reports. Copyright 2007, Life Science Weekly via NewsRx.com.
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