| The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo. | |
| | |
MedLine Citation:
|
PMID: 17331978 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Marie Monet; Valérie Domenga; Barbara Lemaire; Céline Souilhol; Francina Langa; Charles Babinet; Thomas Gridley; Elisabeth Tournier-Lasserve; Michel Cohen-Tannoudji; Anne Joutel |
Related Documents
:
|
17253608 - Rescue of cardioseal pfo closure device malposition with amplatzer pfo closure device a... 19697608 - Echocardiographic assessment of 537 dogs with mitral valve prolapse and leaflet involve... 17980458 - The emergency department occupancy rate: a simple measure of emergency department crowd... 1901788 - Prolongation of xylazine/ketamine induced recumbency time with temazepam in horses. 16397728 - Mycotic aneurysm of the left subclavian artery: ct findings. 8122548 - Giant fusiform aneurysm in middle cerebral artery branches: a report of two cases and a... |
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 |
Affiliation:
|
INSERM U740, Paris F-75010, France. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Aging
/
genetics Animals 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 Mice, Knockout Mutant Proteins / physiology Mutation, Missense Protein Structure, Tertiary / genetics Receptors, Notch / genetics*, metabolism, physiology* Transgenes / physiology |
| Grant Support | |
ID/Acronym/Agency:
|
R01 NS054122/NS/NINDS NIH HHS |
| Chemical | |
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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acet...
Next Document: Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chap...