Mehawej Cybel, Delahodde Agnès, Legeai-Mallet Laurence, Delague Valérie, Kaci Nabil, Desvignes Jean-Pierre, Kibar Zoha, Capo-Chichi José-Mario, Chouery Eliane, Munnich Arnold, Cormier-Daire Valérie, Mégarbané André
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.
University of Paris-Sud, CNRS, UMR 8621, Institute of Genetics and Microbiology, Orsay, France.
PLoS Genet. 2014 May 1;10(5):e1004311. doi: 10.1371/journal.pgen.1004311. eCollection 2014 May.
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.
严格调控的骨化过程受损会导致多种骨骼发育不良，而对其分子基础的解读有助于理解这一复杂过程。在此，我们报告了一种新型严重脊椎发育不良中与线粒体相关的粒细胞巨噬细胞集落刺激因子信号基因（MAGMAS）的纯合突变。MAGMAS，也被称为PAM16（前序列转位酶相关马达16），是一种与线粒体相关的蛋白质，参与前体蛋白转运到线粒体基质的过程。我们发现MAGMAS在发育早期阶段的小梁骨和软骨中特异性表达，且该突变导致蛋白质不稳定。我们进一步证明，此处描述的突变赋予酵母菌株温度敏感表型，损害线粒体基质前体蛋白的导入并诱导细胞死亡。在一种早期致死性骨骼发育不良中发现有害的MAGMAS突变，支持了这种线粒体蛋白在骨化过程中的关键作用。
