Document Detail

The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo.
MedLine Citation:
PMID:  17331978     Owner:  NLM     Status:  MEDLINE    
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). 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. 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.
Marie Monet; Valérie Domenga; Barbara Lemaire; Céline Souilhol; Francina Langa; Charles Babinet; Thomas Gridley; Elisabeth Tournier-Lasserve; Michel Cohen-Tannoudji; Anne Joutel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-03-01
Journal Detail:
Title:  Human molecular genetics     Volume:  16     ISSN:  0964-6906     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2007 Apr 
Date Detail:
Created Date:  2007-05-01     Completed Date:  2007-07-31     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  982-92     Citation Subset:  IM    
INSERM U740, Paris F-75010, France.
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MeSH Terms
Aging / genetics
Arginine / genetics
CADASIL / genetics*,  pathology
Cerebral Arteries / metabolism
Cysteine / genetics
Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
Intracranial Arterial Diseases / genetics,  prevention & control
Lac Operon
Mice, Knockout
Mutant Proteins / physiology
Mutation, Missense
Protein Structure, Tertiary / genetics
Receptors, Notch / genetics*,  metabolism,  physiology*
Transgenes / physiology
Grant Support
Reg. No./Substance:
0/Immunoglobulin J Recombination Signal Sequence-Binding Protein; 0/Mutant Proteins; 0/NOTCH3 protein, human; 0/Receptors, Notch; 52-90-4/Cysteine; 74-79-3/Arginine

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