title: MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers.
abstract: 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.
authors.affiliation: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research at Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA. beggs@enders.tch.harvard.edu
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Johann
authors.initials: J
authors.lastname: Böhm
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Snead
authors.forename: Marek
authors.initials: M
authors.lastname: Kozlowski
authors.forename: Marie
authors.initials: M
authors.lastname: Maurer
authors.forename: Katie
authors.initials: K
authors.lastname: Minor
authors.forename: Martin K
authors.initials: MK
authors.lastname: Childers
authors.forename: Susan M
authors.initials: SM
authors.lastname: Taylor
authors.forename: Christophe
authors.initials: C
authors.lastname: Hitte
authors.forename: James R
authors.initials: JR
authors.lastname: Mickelson
authors.forename: Ling T
authors.initials: LT
authors.lastname: Guo
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mizisin
authors.forename: Anna
authors.initials: A
authors.lastname: Buj-Bello
authors.forename: Laurent
authors.initials: L
authors.lastname: Tiret
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D010375:Pedigree; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D049452:Green Fluorescent Proteins; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin