Journal
NPJ GENOMIC MEDICINE
Volume 7, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41525-022-00307-y
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Funding
- Courtois Foundation
- Fondation du Grand Defi Pierre Lavoie
- Rare Disease Foundation
- Canadian Institute of Health Research
- Neuroscience department of Universite de Montreal
- Fond de recherche du Quebec-Sante
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Despite the increasing accessibility of clinical sequencing, the functional interpretation of gene variants remains challenging for molecular diagnosis of Mendelian diseases. This study identifies a new adult-onset myopathy caused by a nonsense variant in the MLIP gene, and reveals the underlying regulatory mechanisms through RNA sequencing and differential expression analysis.
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.
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