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Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers.

ABSTRACT: Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation. By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagnosed patients with a wide spectrum of myopathies. Seven novel XLMTM patients have been identified, including two girls with an unremarkable family history for myotubular myopathy. Moreover, we have detected and finely mapped a large deletion causing a myotubular myopathy with abnormal genital development. Our data confirm that the severe neonatal onset of the disease in male infants is sufficient to address the direct molecular testing toward the MTM1 gene and, above all, suggest that the number of undiagnosed symptomatic female carriers is probably underestimated.

SUBMITTER: Savarese M

PROVIDER: S-EPMC4862961 | biostudies-literature | 2016 Apr-May

REPOSITORIES: biostudies-literature

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Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers.

Savarese Marco M Musumeci Olimpia O Giugliano Teresa T Rubegni Anna A Fiorillo Chiara C Fattori Fabiana F Torella Annalaura A Battini Roberta R Rodolico Carmelo C Pugliese Aniello A Piluso Giulio G Maggi Lorenzo L D'Amico Adele A Bruno Claudio C Bertini Enrico E Santorelli Filippo Maria FM Mora Marina M Toscano Antonio A Minetti Carlo C Nigro Vincenzo V

Neuromuscular disorders : NMD 20160217 4-5

Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation. By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagn ...[more]

PMID: 27017278

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Project description:BACKGROUND: Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial. METHODS: Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females. RESULTS: The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers. CONCLUSIONS: This is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total DMD transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.

Dataset Information

Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers.

Publications

Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers.

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