title: Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.
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.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Deuquet
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guex
authors.forename: Laurence
authors.initials: L
authors.lastname: Abrami
authors.forename: Suzanne
authors.initials: S
authors.lastname: Salvi
authors.forename: Asvin
authors.initials: A
authors.lastname: Lakkaraju
authors.forename: Maria Celeste M
authors.initials: MC
authors.lastname: Ramirez
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.forename: Dariusz
authors.initials: D
authors.lastname: Rokicki
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafe
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Françoise G
authors.initials: FG
authors.lastname: van der Goot
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D057770:Hyaline Fibromatosis Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D061988:Proteasome Inhibitors; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D018000:Receptors, Peptide
chemical_list: C447150:ANTXR2 protein, human; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D061988:Proteasome Inhibitors; D018000:Receptors, Peptide