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A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy
Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene (NEB) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alt...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239344/ https://www.ncbi.nlm.nih.gov/pubmed/34211429 http://dx.doi.org/10.3389/fneur.2021.660113 |
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author | Laflamme, Nathalie Lace, Baiba Thonta Setty, Samarth Rioux, Nadie Labrie, Yvan Droit, Arnaud Chrestian, Nicolas Rivest, Serge |
author_facet | Laflamme, Nathalie Lace, Baiba Thonta Setty, Samarth Rioux, Nadie Labrie, Yvan Droit, Arnaud Chrestian, Nicolas Rivest, Serge |
author_sort | Laflamme, Nathalie |
collection | PubMed |
description | Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene (NEB) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the NEB. The variant was predicted by in silico tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy. |
format | Online Article Text |
id | pubmed-8239344 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82393442021-06-30 A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy Laflamme, Nathalie Lace, Baiba Thonta Setty, Samarth Rioux, Nadie Labrie, Yvan Droit, Arnaud Chrestian, Nicolas Rivest, Serge Front Neurol Neurology Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene (NEB) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the NEB. The variant was predicted by in silico tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy. Frontiers Media S.A. 2021-06-15 /pmc/articles/PMC8239344/ /pubmed/34211429 http://dx.doi.org/10.3389/fneur.2021.660113 Text en Copyright © 2021 Laflamme, Lace, Thonta Setty, Rioux, Labrie, Droit, Chrestian and Rivest. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neurology Laflamme, Nathalie Lace, Baiba Thonta Setty, Samarth Rioux, Nadie Labrie, Yvan Droit, Arnaud Chrestian, Nicolas Rivest, Serge A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy |
title | A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy |
title_full | A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy |
title_fullStr | A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy |
title_full_unstemmed | A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy |
title_short | A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy |
title_sort | homozygous deep intronic mutation alters the splicing of nebulin gene in a patient with nemaline myopathy |
topic | Neurology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239344/ https://www.ncbi.nlm.nih.gov/pubmed/34211429 http://dx.doi.org/10.3389/fneur.2021.660113 |
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