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Hum Mol Genet. 2001 Feb 15;10(4):405-13.

Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome.

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  • 1Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia, 1006 Abramson Research Center, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA.

Abstract

Jagged1 (JAG1) is a cell surface ligand in the Notch signaling pathway and mutations 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 ( approximately 6%), 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 on protein 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 wild-type JAG1. Neither R184H or L37S is present on the cell surface and both are abnormally glycosylated. Furthermore, these mutations lead to abnormal accumulation of the protein, possibly in the endoplasmic reticulum. Both P163L and 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.

PMID:
11157803
[PubMed - indexed for MEDLINE]
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