title: Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation.
abstract: We have investigated a woman and her daughter with an early onset, slowly progressive myopathy. Muscle biopsy showed in both cases severe atrophy with marked fatty replacement. Frequent fibers with internalized nuclei were present but no typical features of centronuclear myopathy. There were also many fibers with deep invaginations of the plasma membrane. The presence of necklace fibers provided clue to correct genetic diagnosis. Both patients had a novel heterozygous splice site mutation in the myotubularin gene, MTM1 (c.867+1G>T). Analysis of MTM1 cDNA revealed that the mutation resulted in aberrant splicing with variable exon skipping. The expression of normal transcripts was markedly reduced and there was reduced expression of myotubularin protein. Although the expression of the allele without the mutation was reduced we did not obtain evidence of skewed X-chromosome inactivation. Other factors than skewed X-inactivation may cause allele inactivation and manifestation of severe myopathy in heterozygous carriers of pathogenic MTM1 mutations.
authors.affiliation: Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. carola.hedberg@gu.se
authors.forename: Carola
authors.initials: C
authors.lastname: Hedberg
authors.forename: Christopher
authors.initials: C
authors.lastname: Lindberg
authors.forename: Gyöngyvér
authors.initials: G
authors.lastname: Máthé
authors.forename: Ali-Reza
authors.initials: AR
authors.lastname: Moslemi
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
mesh_terms: D000368:Aged; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009035:Mothers; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009679:Nuclear Family; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin