The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia

PLoS Genet. 2014 May 1;10(5):e1004311. doi: 10.1371/journal.pgen.1004311. eCollection 2014 May.

Abstract

Impairment of the tightly regulated ossification process leads to a wide range of skeletal dysplasias and deciphering their molecular bases has contributed to the understanding of this complex process. Here, we report a homozygous mutation in the mitochondria-associated granulocyte macrophage colony stimulating factor-signaling gene (MAGMAS) in a novel and severe spondylodysplastic dysplasia. MAGMAS, also referred to as PAM16 (presequence translocase-associated motor 16), is a mitochondria-associated protein involved in preprotein translocation into the matrix. We show that MAGMAS is specifically expressed in trabecular bone and cartilage at early developmental stages and that the mutation leads to an instability of the protein. We further demonstrate that the mutation described here confers to yeast strains a temperature-sensitive phenotype, impairs the import of mitochondrial matrix pre-proteins and induces cell death. The finding of deleterious MAGMAS mutations in an early lethal skeletal dysplasia supports a key role for this mitochondrial protein in the ossification process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bone Diseases, Developmental / diagnostic imaging
  • Bone Diseases, Developmental / genetics*
  • Exome
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / physiology*
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • RNA, Messenger / genetics
  • Radiography
  • Saccharomyces cerevisiae / genetics
  • Sequence Homology, Amino Acid

Substances

  • Mitochondrial Proteins
  • RNA, Messenger
  • magmas protein, human

Grant support

CM was supported by the “Agence Universitaire de la Francophonie”. We also thank the “Association Médicale Franco-Libanaise” and the “Conseil de Recherche de l'Université Saint-Joseph” for their funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.