Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.

Details

Ressource 1Download: BIB_27DB154B3E2F.P001.pdf (887.81 [Ko])
State: Public
Version: author
Serval ID
serval:BIB_27DB154B3E2F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.
Journal
Embo Molecular Medicine
Author(s)
Deuquet J., Lausch E., Guex N., Abrami L., Salvi S., Lakkaraju A., Ramirez M.C., Martignetti J.A., Rokicki D., Bonafe L., Superti-Furga A., van der Goot F.G.
ISSN
1757-4684 (Electronic)
ISSN-L
1757-4676
Publication state
Published
Issued date
2011
Volume
3
Number
4
Pages
208-221
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
Hyaline Fibromatosis Syndrome (HFS) is a human genetic disease caused by mutations in the anthrax toxin receptor 2 (or cmg2) gene, which encodes a membrane protein thought to be involved in the homeostasis of the extracellular matrix. Little is known about the structure and function of the protein or the genotype-phenotype relationship of the disease. Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level. Altogether, we show that missense mutations that map to the extracellular von Willebrand domain or the here characterized Ig-like domain of CMG2 lead to folding defects and thereby to retention of the mutated protein in the endoplasmic reticulum (ER). Mutations in the Ig-like domain prevent proper disulphide bond formation and are more efficiently targeted to ER-associated degradation. Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS.
Pubmed
Web of science
Open Access
Yes
Create date
14/03/2011 13:35
Last modification date
03/12/2020 16:53
Usage data