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Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing

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-in...

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Autores principales: Mezreani, Jean, Audet, Sébastien, Martin, Florence, Charbonneau, Jade, Triassi, Valérie, Bareke, Eric, Laplante, Annie, Karamchandani, Jason, Massie, Rami, Chalk, Colin H., O’Ferrall, Erin, Tétreault, Martine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174206/
https://www.ncbi.nlm.nih.gov/pubmed/35672413
http://dx.doi.org/10.1038/s41525-022-00307-y
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author Mezreani, Jean
Audet, Sébastien
Martin, Florence
Charbonneau, Jade
Triassi, Valérie
Bareke, Eric
Laplante, Annie
Karamchandani, Jason
Massie, Rami
Chalk, Colin H.
O’Ferrall, Erin
Tétreault, Martine
author_facet Mezreani, Jean
Audet, Sébastien
Martin, Florence
Charbonneau, Jade
Triassi, Valérie
Bareke, Eric
Laplante, Annie
Karamchandani, Jason
Massie, Rami
Chalk, Colin H.
O’Ferrall, Erin
Tétreault, Martine
author_sort Mezreani, Jean
collection PubMed
description 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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spelling pubmed-91742062022-06-09 Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing Mezreani, Jean Audet, Sébastien Martin, Florence Charbonneau, Jade Triassi, Valérie Bareke, Eric Laplante, Annie Karamchandani, Jason Massie, Rami Chalk, Colin H. O’Ferrall, Erin Tétreault, Martine NPJ Genom Med Case Report 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. Nature Publishing Group UK 2022-06-07 /pmc/articles/PMC9174206/ /pubmed/35672413 http://dx.doi.org/10.1038/s41525-022-00307-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Case Report
Mezreani, Jean
Audet, Sébastien
Martin, Florence
Charbonneau, Jade
Triassi, Valérie
Bareke, Eric
Laplante, Annie
Karamchandani, Jason
Massie, Rami
Chalk, Colin H.
O’Ferrall, Erin
Tétreault, Martine
Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing
title Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing
title_full Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing
title_fullStr Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing
title_full_unstemmed Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing
title_short Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing
title_sort novel homozygous nonsense mutation of mlip and compensatory alternative splicing
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174206/
https://www.ncbi.nlm.nih.gov/pubmed/35672413
http://dx.doi.org/10.1038/s41525-022-00307-y
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