MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2010

MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers.

Marie Maurer
Anna Buj-Bello
Laurent Tiret

Résumé

Mutations in the MTM1 gene encoding myotubularin cause X-linked myotubular myopathy (XLMTM), a well-defined subtype of human centronuclear myopathy. Seven male Labrador Retrievers, age 14-26 wk, were clinically evaluated for generalized weakness and muscle atrophy. Muscle biopsies showed variability in fiber size, centrally placed nuclei resembling fetal myotubes, and subsarcolemmal ringed and central dense areas highlighted with mitochondrial specific reactions. Ultrastructural studies confirmed the centrally located nuclei, abnormal perinuclear structure, and mitochondrial accumulations. Wild-type triads were infrequent, with most exhibiting an abnormal orientation of T tubules. MTM1 gene sequencing revealed a unique exon 7 variant in all seven affected males, causing a nonconservative missense change, p.N155K, which haplotype data suggest derives from a recent founder in the local population. Analysis of a worldwide panel of 237 unaffected Labrador Retrievers and 59 additional control dogs from 25 other breeds failed to identify this variant, supporting it as the pathogenic mutation. Myotubularin protein levels and localization were abnormal in muscles from affected dogs, and expression of GFP-MTM1 p.N155K in COS-1 cells showed that the mutant protein was sequestered in proteasomes, where it was presumably misfolded and prematurely degraded. These data demonstrate that XLMTM in Labrador Retrievers is a faithful genetic model of the human condition.

Domaines

Génétique
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Dates et versions

inserm-00511900 , version 1 (31-08-2010)

Identifiants

Citer

Alan H. Beggs, Johann Böhm, Elizabeth Snead, Marek Kozlowski, Marie Maurer, et al.. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers.. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107 (33), pp.14697-702. ⟨10.1073/pnas.1003677107⟩. ⟨inserm-00511900⟩
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