A Deep Intronic Variant Activates a Pseudoexon in the MTM1Gene in a Family with X-Linked Myotubular Myopathy

Abstract

We report a novel intronic variant in the <i>MTM1</i> 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 mature <i>MTM1</i> 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 <i>MTM1</i> 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.