title: Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype.
abstract: X-linked myotubular myopathy is characterised by neonatal hypotonia, muscle weakness and respiratory distress in affected males, leading often to early death, although prolonged survival is observed in milder forms, or as a result of prolongation of ventilation support. It is caused by mutations in the MTM1 gene, which encodes a phosphatase called myotubularin, which has been highly conserved during evolution, down to yeasts ( S. cerevisiae and S. pombe). To date, 251 mutations have been identified in unrelated families, corresponding to 158 different disease-associated mutations, which are widespread throughout the gene. We have found additional mutations in 77 patients, including 35 novel ones. We identified a missense mutation N180K in a 67-year-old grandfather (the oldest known patient with an MTM1 mutation), previously suspected to have autosomal centronuclear myopathy, and in his two grandsons also mildly affected. Mild and moderate phenotypes associated with novel missense mutations and with a translation initiation defect mutation are discussed, as well as severe phenotypes associated with particular novel mutations. With the present report, 192 different mutations in the MTM1 gene have been described in 328 families. The spectrum of mutations is now enlarged from the very severe classic neonatal phenotype to very mild phenotype allowing survival to the age of 67 years.
authors.affiliation: Laboratoire de Diagnostic Génétique, Faculté de Médecine et CHRU, Strasbourg, France. bianca@igbmc.u-strasbg.fr
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.forename: Sabina
authors.initials: S
authors.lastname: Gallati
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.forename: Anna
authors.initials: A
authors.lastname: Buj-Bello
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D004247:DNA / Q000097:blood / Q000302:isolation & purification; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D017384:Sequence Deletion
chemical_list: D004247:DNA; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin