The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia. C. Mehawej1,2, A. Delahodde3, L. Legeai-Mallet2, V. Delague4,5, N. Kaci2, J.-P. Desvignes4,5, Z. Kibar6,7, J.-M. Capo-Chichi6,7, E. Chouery1, A. Munnich2, V. Cormier-Daire2, A. Mégarbané1 1) Unité de Génétique Médicale et Laboratoire International associé INSERM à lUnité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon; 2) Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris 75015, France; 3) University of Paris-Sud, CNRS, UMR 8621, Institute of Genetics and Microbiology, Orsay, 91405, France; 4) Inserm, UMR_S 910, 13385, Marseille, France; 5) Aix Marseille Université, GMGF, 13385, Marseille, France; 6) Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada; 7) Department of Obstetrics and Gynecology, Université de Montréal, Montréal, Canada.

   Impairment of the tightly regulated ossification process leads to a wide range of skeletal dysplasias (SD). Deciphering the molecular basis of a considerable number of SD contributes to the understanding of this complex process. Here, we report the identification of a homozygous mutation in the mitochondria-associated granulocyte macrophage colony stimulating factor-signaling gene MAGMAS (NM_016069: c.A226G; p.Asn76Asp) in a novel and severe spondylometaphyseal dysplasia, recently reported by Mégarbané et al. 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. Our finding of deleterious MAGMAS mutations in an early lethal skeletal dysplasia establishes for the first time a link between a mitochondrial protein and skeletal dysplasias and supports a key role for MAGMAS in the ossification process.

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