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Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing

2022; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/s41525-022-00307-y

2056-7944

Jean Mezreani, Sébastien Audet, Florence Martin, Jade Charbonneau, Valérie Triassi, Eric Bareke, Annie Laplante, Jason Karamchandani, Rami Massie, Colin Chalk, Erin O’Ferrall, Martine Tétreault,

Neurogenetic and Muscular Disorders Research

Despite the growing accessibility of clinical sequencing, functional interpretation of variants remains a major hurdle to molecular diagnostics of Mendelian diseases. We aimed to describe a new adult-onset myopathy with muscle weakness and hyperCKemia caused by a nonsense variant in muscular LMNA-interacting protein (MLIP). Following RNA-sequencing, differential expression analysis uncovered a significant downregulation of this gene, which had a surprisingly mild effect on MLIP protein expression. RT-PCR and long-read sequencing (LRS) both support an important transcriptome shift in the patient, where decreased MLIP levels are seemingly due to nonsense-mediated decay of transcripts containing the exon 5 mutation. Moreover, a compensatory mechanism upregulates the functionally lacking isoforms and generates novel transcripts. These results support the recently discovered clinical implications of MLIP variants in myopathies, highlighting for the first time its relevance in adult-onset cases. These results also underline the power of LRS as a tool for the functional assessment of variants of unknown significance (VUS), as well as the definition of accurate isoform profile annotations in a tissue-specific manner.