The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia.
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.
Unité de Génétique Médicale et Laboratoire International associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon; Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris, France.
Cybel
C
Mehawej
University of Paris-Sud, CNRS, UMR 8621, Institute of Genetics and Microbiology, Orsay, France.
Agnès
A
Delahodde
Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris, France.
Laurence
L
Legeai-Mallet
Inserm, UMR_S 910, Marseille, France; Aix Marseille Université, GMGF, Marseille, France.
Valérie
V
Delague
Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris, France.
Nabil
N
Kaci
Inserm, UMR_S 910, Marseille, France; Aix Marseille Université, GMGF, Marseille, France.
Jean-Pierre
JP
Desvignes
Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada; Department of Obstetrics and Gynecology, Université de Montréal, Montréal, Canada.
Zoha
Z
Kibar
Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada; Department of Obstetrics and Gynecology, Université de Montréal, Montréal, Canada.
José-Mario
JM
Capo-Chichi
Unité de Génétique Médicale et Laboratoire International associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon.
Eliane
E
Chouery
Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris, France.
Arnold
A
Munnich
Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris, France.
Valérie
V
Cormier-Daire
Unité de Génétique Médicale et Laboratoire International associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon.
André
A
Mégarbané
D000595:Amino Acid Sequence; D000818:Animals; D001848:Bone Diseases, Developmental / Q000000981:diagnostic imaging / Q000235:genetics*; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D011859:Radiography; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C503439:PAM16 protein, human; D012333:RNA, Messenger