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

We report a novel intronic variant in theMTM1 gene in 4 males in a family with severe X-linked myotubular myopathy. The A#x3e;G variant in deep intronic space activates a cryptic 5 ′ donor splice site resulting in the inclusion of a 48-bp pseudoexon into the matureMTM1 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 ofMTM1 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.Mol Syndromol
Source: Molecular Syndromology - Category: Molecular Biology Source Type: research