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Titolo:
Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome
Autore:
Morrissette, JJD; Colliton, RP; Spinner, NB;
Indirizzi:
Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Abramson Res Ctr 1006, Philadelphia, PA 19104 USA Childrens Hosp Philadelphia Philadelphia PA USA 19104 lphia, PA 19104 USA
Titolo Testata:
HUMAN MOLECULAR GENETICS
fascicolo: 4, volume: 10, anno: 2001,
pagine: 405 - 413
SICI:
0964-6906(20010215)10:4<405:DITAPO>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
GLYCOSYLATION SITES; NOTCH3 MUTATIONS; CADASIL PATIENTS; DELTA-HOMOLOG; JAGGED1 GENE; RECEPTOR; CALCIUM; DEGRADATION; FIBRILLIN-1; DELETIONS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Spinner, NB Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Abramson Res Ctr 1006, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA Childrens Hosp Philadelphia 34th St & Civ Ctr Blvd Philadelphia PA USA 19104
Citazione:
J.J.D. Morrissette et al., "Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome", HUM MOL GEN, 10(4), 2001, pp. 405-413

Abstract

Jagged1 (JAG1) is a cell surface ligand in the Notch signaling pathway andmutations in this gene cause Alagille syndrome (AGS), JAG1 mutations have been identified in 60-70% of AGS patients studied, and these include total gene deletions (similar to6%), protein-truncating mutations (insertions, deletions and nonsense mutations) (82%) and missense mutations (12%), Based on the finding that total JAG1 deletions cause AGS, haploinsufficiency has been hypothesized to be a mechanism for disease causation; however, the mechanism by which missense mutations cause disease is not understood. To date,25 unique missense mutations have been observed in AGS patients. Missense mutations are non-randomly distributed across the protein with clusters at the 5' end of the protein, in the conserved DSL domain, and two clusters within the EGF repeats. To understand the effect of the missense mutations onprotein localization and function, we have studied four missense mutations(R184H, L37S, P163L and P871R). In two assays of JAG1 function, R184H and L37S are associated with loss of Notch signaling activity relative to wildtype JAG1, Neither R184H or L37S is present on the cell surface and both areabnormally glycosylated, Furthermore, these mutations lead to abnormal accumulation of the protein, possibly in the endoplasmic reticulum. Both P163Land P871R are associated with normal levels of Notch signaling activity and are present on the cell surface, consistent with these changes being polymorphisms rather than disease-causing mutations.

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Documento generato il 05/07/20 alle ore 07:11:28