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Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis

The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of periph...

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Autores principales: Boso, Federica, Taioli, Federica, Cabrini, Ilaria, Cavallaro, Tiziana, Fabrizi, Gian Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824018/
https://www.ncbi.nlm.nih.gov/pubmed/33375465
http://dx.doi.org/10.3390/brainsci11010024
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author Boso, Federica
Taioli, Federica
Cabrini, Ilaria
Cavallaro, Tiziana
Fabrizi, Gian Maria
author_facet Boso, Federica
Taioli, Federica
Cabrini, Ilaria
Cavallaro, Tiziana
Fabrizi, Gian Maria
author_sort Boso, Federica
collection PubMed
description The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5′ untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5′ UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels.
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spelling pubmed-78240182021-01-24 Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis Boso, Federica Taioli, Federica Cabrini, Ilaria Cavallaro, Tiziana Fabrizi, Gian Maria Brain Sci Article The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5′ untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5′ UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels. MDPI 2020-12-27 /pmc/articles/PMC7824018/ /pubmed/33375465 http://dx.doi.org/10.3390/brainsci11010024 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Boso, Federica
Taioli, Federica
Cabrini, Ilaria
Cavallaro, Tiziana
Fabrizi, Gian Maria
Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis
title Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis
title_full Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis
title_fullStr Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis
title_full_unstemmed Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis
title_short Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis
title_sort aberrant splicing in gjb1 and the relevance of 5′ utr in cmtx1 pathogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824018/
https://www.ncbi.nlm.nih.gov/pubmed/33375465
http://dx.doi.org/10.3390/brainsci11010024
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