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Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients

Limb–girdle muscular dystrophy type R1 (LGMDR1) is caused by mutations in CAPN3 and is the most common type of recessive LGMD. Even with the use of whole-exome sequencing (WES), only one mutant allele of CAPN3 is found in a significant number of LGMDR patients. This points to a role of non-coding, i...

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Autores principales: Macias, Anna, Fichna, Jakub Piotr, Topolewska, Malgorzata, Rȩdowicz, Maria J., Kaminska, Anna M., Kostera-Pruszczyk, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551377/
https://www.ncbi.nlm.nih.gov/pubmed/34720847
http://dx.doi.org/10.3389/fnins.2021.692482
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author Macias, Anna
Fichna, Jakub Piotr
Topolewska, Malgorzata
Rȩdowicz, Maria J.
Kaminska, Anna M.
Kostera-Pruszczyk, Anna
author_facet Macias, Anna
Fichna, Jakub Piotr
Topolewska, Malgorzata
Rȩdowicz, Maria J.
Kaminska, Anna M.
Kostera-Pruszczyk, Anna
author_sort Macias, Anna
collection PubMed
description Limb–girdle muscular dystrophy type R1 (LGMDR1) is caused by mutations in CAPN3 and is the most common type of recessive LGMD. Even with the use of whole-exome sequencing (WES), only one mutant allele of CAPN3 is found in a significant number of LGMDR patients. This points to a role of non-coding, intronic or regulatory, sequence variants in the disease pathogenesis. Targeted sequencing of the whole CAPN3 gene including not only intronic, 3′ and 5′ UTRs but also potential regulatory regions was performed in 27 patients suspected with LGMDR1. This group included 13 patients with only one mutated CAPN3 allele detected previously with exome sequencing. A second rare variant in the non-coding part of CAPN3 was found in 11 of 13 patients with previously identified single mutation. Intronic mutations were found in 10 cases, with c.1746-20C>G variant present in seven patients. In addition, a large deletion of exons 2–8 was found in one patient. In the patients with no causative mutation previously found, we detected rare CAPN3 variants in 5 out of 10 patients and in two of them in a compound heterozygous state. Rare variants within putative regulatory sequences distant from the CAPN3 gene were found in 15 patients, although in 11 of these cases, other variants are deemed causative. The results indicate that intronic mutations are common in Polish LGMDR patients, and testing for non-coding mutations in CAPN3 should be performed in apparently single heterozygous patients.
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spelling pubmed-85513772021-10-29 Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients Macias, Anna Fichna, Jakub Piotr Topolewska, Malgorzata Rȩdowicz, Maria J. Kaminska, Anna M. Kostera-Pruszczyk, Anna Front Neurosci Neuroscience Limb–girdle muscular dystrophy type R1 (LGMDR1) is caused by mutations in CAPN3 and is the most common type of recessive LGMD. Even with the use of whole-exome sequencing (WES), only one mutant allele of CAPN3 is found in a significant number of LGMDR patients. This points to a role of non-coding, intronic or regulatory, sequence variants in the disease pathogenesis. Targeted sequencing of the whole CAPN3 gene including not only intronic, 3′ and 5′ UTRs but also potential regulatory regions was performed in 27 patients suspected with LGMDR1. This group included 13 patients with only one mutated CAPN3 allele detected previously with exome sequencing. A second rare variant in the non-coding part of CAPN3 was found in 11 of 13 patients with previously identified single mutation. Intronic mutations were found in 10 cases, with c.1746-20C>G variant present in seven patients. In addition, a large deletion of exons 2–8 was found in one patient. In the patients with no causative mutation previously found, we detected rare CAPN3 variants in 5 out of 10 patients and in two of them in a compound heterozygous state. Rare variants within putative regulatory sequences distant from the CAPN3 gene were found in 15 patients, although in 11 of these cases, other variants are deemed causative. The results indicate that intronic mutations are common in Polish LGMDR patients, and testing for non-coding mutations in CAPN3 should be performed in apparently single heterozygous patients. Frontiers Media S.A. 2021-10-14 /pmc/articles/PMC8551377/ /pubmed/34720847 http://dx.doi.org/10.3389/fnins.2021.692482 Text en Copyright © 2021 Macias, Fichna, Topolewska, Rȩdowicz, Kaminska and Kostera-Pruszczyk. 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 Neuroscience
Macias, Anna
Fichna, Jakub Piotr
Topolewska, Malgorzata
Rȩdowicz, Maria J.
Kaminska, Anna M.
Kostera-Pruszczyk, Anna
Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients
title Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients
title_full Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients
title_fullStr Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients
title_full_unstemmed Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients
title_short Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb–Girdle Muscular Dystrophy Patients
title_sort targeted next-generation sequencing reveals mutations in non-coding regions and potential regulatory sequences of calpain-3 gene in polish limb–girdle muscular dystrophy patients
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551377/
https://www.ncbi.nlm.nih.gov/pubmed/34720847
http://dx.doi.org/10.3389/fnins.2021.692482
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