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

Alan H. Beggs, Johann Böhm, Elizabeth Snead, Marek Kozlowski, Marie Maurer, Katie Minor, Martin K. Childers, Susan M. Taylor, Christophe Hitte, James R. Mickelson, Ling T. Guo, Andrew P. Mizisin, Anna Buj-Bello, Laurent Tiret, Jocelyn Laporte, G. Diane Shelton

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87 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)14697-14702
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
StatePublished - Aug 17 2010


  • Animal model
  • Canine myopathy
  • Congenital myopathy
  • Myotubularin
  • Necklace fibers


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