Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype

• Published in: European journal of human genetics : EJHG 2012-06, Vol.20 (6), p.701-704
• Main Authors: VASLI, Nasim, LAUGEL, Vincent, BÖHM, Johann, LANNES, Béatrice, BIANCALANA, Valérie, LAPORTE, Jocelyn
• Format: Article
• Language: English
• Subjects: Alternative splicing; Antibodies; Base Sequence; Biological and medical sciences; Biopsy; Child, Preschool; Congenital diseases; Deoxyribonucleic acid; Diagnosis; DNA; DNA sequencing; Exons; Female; Fundamental and applied biological sciences. Psychology; Genetic screening; Genetics; Genetics of eukaryotes. Biological and molecular evolution; genomics; Genotype & phenotype; Hereditary diseases; Humans; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; MTM1 gene; Mutation; Myopathies, Structural, Congenital - genetics; Myopathy; Patients; Phenotypes; Phosphatase; Point mutation; Polymerase chain reaction; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Splicing; RNA, Messenger - metabolism; Short Report; Splicing; Transcription; Western blotting; X chromosome
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2011.256

Mutations impacting on the splicing of pre-mRNA are one important cause of genetically inherited diseases. However, detection of splice mutations, that are mainly due to intronic variations, and characterization of their effects are usually not performed as a first approach during genetic diagnosis. X-linked recessive myotubular myopathy is a severe congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. Here, we screened a male patient showing an unusually mild phenotype without respiratory distress by western blot with specific myotubularin antibodies and detected a strong reduction of the protein level.The disease was subsequently linked to a hemizygous point mutation affecting the acceptor splice site of exon 8 of MTM1, proven by protein, transcript and genomic DNA analysis. Detailed analysis of the MTM1 mRNA by RT-PCR, sequencing and quantitative PCR revealed multiple abnormal transcripts with retention of a truncated exon 8, and neighboring exons 7 and 9 but exclusion of several other exons, suggesting a complex effect of this mutation on the splicing of non-adjacent exons. We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants. It is likely that complex splice aberrations due to a single mutation also account for unsolved cases in other diseases.