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Titolo:
CADASIL: Genetics and pathophysiology
Autore:
Joutel, A; Francois, A; Chabriat, H; Vahedi, K; Andreux, F; Domenga, V; Cecillon, M; Maciazek, J; Bousser, MG; Tournier-Lasserve, E;
Indirizzi:
Hop Lariboisiere, INSERM, EPI 99 21, F-75475 Paris 10, France Hop Lariboisiere Paris France 10 RM, EPI 99 21, F-75475 Paris 10, France
Titolo Testata:
BULLETIN DE L ACADEMIE NATIONALE DE MEDECINE
fascicolo: 7, volume: 184, anno: 2000,
pagine: 1535 - 1544
SICI:
0001-4079(2000)184:7<1535:CGAP>2.0.ZU;2-P
Fonte:
ISI
Lingua:
FRE
Soggetto:
AUTOSOMAL-DOMINANT ARTERIOPATHY; SUBCORTICAL INFARCTS; NOTCH3 MUTATIONS; LEUKOENCEPHALOPATHY; STROKE;
Keywords:
cerebral infarction; dementia, multi-infarct; leukoencephalopathy; migraine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
8
Recensione:
Indirizzi per estratti:
Indirizzo: Joutel, A Hop Lariboisiere, INSERM, EPI 99 21, 2 Rue Ambroise Pare, F-75475 Paris 10, France Hop Lariboisiere 2 Rue Ambroise Pare Paris France 10 10, France
Citazione:
A. Joutel et al., "CADASIL: Genetics and pathophysiology", B ACA N MED, 184(7), 2000, pp. 1535-1544

Abstract

CADASIL, an autosomal dominant adult onset arteriopathy causing stroke anddementia in humans, is underlaid by a non atherosclerotic non amyloid angiopathy involving mainly the media of small cerebral arteries; it is characterized by major lesions of vascular smooth muscle cells. Using a positionalcloning approach, we mapped CADASIL locus on chromosome 19 and identified the mutated gene as being Notch3. This gene, previously unknown in humans, encodes for a large transmembrane receptor belonging to the Notch/lin12 gene family which are known to be involved in cell fate specification during development. Genetic analysis of more than 120 CADASIL unrelated families allowed 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 molecular diagnostic test has been set up and is now widely required by clinicians involved in the diagnosis of vascular leukoencephalopathies. Using this test, we recently showed that CADASIL can also occur in patients who donot have any affected relative due to the existence of notch3 de novo mutations. As a first step to investigate the molecular and cellular mechanismsleading from Notch3 mutations to CADASIL phenotype, we analyzed by in-situhybridization and immunohistochemistry the pattern of expression of this gene. Notch3 expression is highly restricted to the vascular smooth muscle cell in normal human adults. In CADASIL tissues there is a dramatic accumulation of the extracellular domain of the protein which suggests that one of the main mechanisms of CADASIL involves anomalies in the proteolytical cleavage and clearance of this protein. These data provide important clues to the mechanisms of this condition mid current work should lead in the next future to a complete understanding of CADASIL and set up the basis of a rational therapeutical approach of this condition.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/09/20 alle ore 00:11:32