Open AccessHyaline Fibromatosis Syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors
Author(s) -
Deuquet Julie,
Lausch Ekkehart,
Guex Nicolas,
Abrami Laurence,
Salvi Suzanne,
Lakkaraju Asvin,
Ramirez Maria Celeste M.,
Martignetti John A.,
Rokicki Dariusz,
Bonafe Luisa,
SupertiFurga Andrea,
van der Goot Françoise G.
Publication year - 2011
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201100124
Subject(s) - ectodomain , endoplasmic reticulum , tetraspanin , microbiology and biotechnology , mutant , anthrax toxin , biology , unfolded protein response , proteasome , chemistry , receptor , gene , genetics , fusion protein , cell , recombinant dna
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.