Dataset Information

A Deep Intronic Variant Activates a Pseudoexon in the MTM1 Gene in a Family with X-Linked Myotubular Myopathy.

ABSTRACT: We report a novel intronic variant in the MTM1 gene in 4 males in a family with severe X-linked myotubular myopathy. The A>G variant in deep intronic space activates a cryptic 5' donor splice site resulting in the inclusion of a 48-bp pseudoexon into the mature MTM1 mRNA. The variant is present in all affected males, absent in unaffected males, and heterozygous in the mother of the affected males. The included intronic sequence contains a premature stop codon, and experiments using a translational inhibitor indicate that the mutant mRNAs undergo nonsense-mediated decay. We conclude that affected males produce no, or low, levels of MTM1 mRNA likely leading to a significant reduction of myotubularin-1 protein resulting in the severe neonatal myopathy present in this family. The study highlights the need to consider noncoding variants in genomic screening in families with X-linked myotubular myopathy.

SUBMITTER: Fitzgerald J

PROVIDER: S-EPMC7802444 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Deep Intronic Variant Activates a Pseudoexon in the MTM1 Gene in a Family with X-Linked Myotubular Myopathy.

Fitzgerald Jamie J Feist Cori C Dietz Paula P Moore Stephen S Basel Donald D

Molecular syndromology 20200916 5-6

We report a novel intronic variant in the MTM1 gene in 4 males in a family with severe X-linked myotubular myopathy. The A>G variant in deep intronic space activates a cryptic 5' donor splice site resulting in the inclusion of a 48-bp pseudoexon into the mature MTM1 mRNA. The variant is present in all affected males, absent in unaffected males, and heterozygous in the mother of the affected males. The included intronic sequence contains a premature stop codon, and experiments using ...[more]

PMID: 33505229

Similar Datasets

Project description:BackgroundCongenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency. In fact, canine models of dystrophin deficient muscular dystrophy and X-linked myotubular myopathy are of tremendous value in the translation of new and promising therapies for the treatment of these diseases. We have recently identified a family of Australian Rottweilers in which male puppies were clinically affected with severe muscle weakness and atrophy that resulted in early euthanasia or death. X-linked myotubular myopathy was suspected based on the early and severe clinical presentation and histopathological changes within muscle biopsies. The aim of this study was to determine the genetic basis for myopathy in these dogs and compare and contrast the clinical presentation, histopathology, ultrastructure, and mutation in this family of Rottweiler dogs with the previously described myotubular myopathy in Labrador retrievers.ResultsHistopathology, histochemistry, and ultrastructural examination of muscle biopsies from affected Rottweiler puppies were consistent with an X-linked myotubular myopathy. An unusual finding that differed from the previously reported Labradors and similar human cases was the presence of excessive autophagy and prominent autophagic vacuoles. Molecular investigations confirmed a missense mutation in exon 11 of MTM1 that was predicted to result in a non-functional phosphatase activity. Although the clinical presentations and histopathology were similar, the MTM1 p.(Q384P) mutation is different from the p.(N155K) mutation in exon 7 affecting Labrador retrievers with X-linked myotubular myopathy.ConclusionsHere we describe a second pathogenic mutation in MTM1 causing X-linked myotubular myopathy in dogs. Our findings suggest a variety of MTM1 mutations in dogs as seen in human patients. The number of MTM1 mutations resulting in similar severe and progressive clinical myopathy and histopathological changes are likely to increase as canine myopathies are further characterized.

Dataset Information

A Deep Intronic Variant Activates a Pseudoexon in the MTM1 Gene in a Family with X-Linked Myotubular Myopathy.

Publications

A Deep Intronic Variant Activates a Pseudoexon in the <i>MTM1</i> Gene in a Family with X-Linked Myotubular Myopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets