Hyaline Fibromatosis Syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors

Julie Deuquet, Ekkehart Lausch, Nicolas Guex, Laurence Abrami, Suzanne Salvi, Asvin Lakkaraju, Maria Celeste M. Ramirez, John A. Martignetti, Dariusz Rokicki, Luisa Bonafe, Andrea Superti-Furga, Françoise G. Van der Goot

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish
Pages (from-to)208-221
Number of pages14
JournalEMBO Molecular Medicine
Volume3
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • CMG2
  • Conformational disease
  • Protein folding

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