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Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy

X-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the n...

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Autores principales: Bosco, Luca, Leone, Daniela, Costa Comellas, Laura, Monforte, Mauro, Pane, Marika, Mercuri, Eugenio, Bertini, Enrico, D’Amico, Adele, Fattori, Fabiana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499315/
https://www.ncbi.nlm.nih.gov/pubmed/36142184
http://dx.doi.org/10.3390/ijms231810274
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author Bosco, Luca
Leone, Daniela
Costa Comellas, Laura
Monforte, Mauro
Pane, Marika
Mercuri, Eugenio
Bertini, Enrico
D’Amico, Adele
Fattori, Fabiana
author_facet Bosco, Luca
Leone, Daniela
Costa Comellas, Laura
Monforte, Mauro
Pane, Marika
Mercuri, Eugenio
Bertini, Enrico
D’Amico, Adele
Fattori, Fabiana
author_sort Bosco, Luca
collection PubMed
description X-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the novel hemizygous MTM1 c.1261-5T>G intronic variant, which interferes with the normal splicing process, generating two different abnormal transcripts simultaneously expressed in the patient’s muscular cells. The first aberrant transcript, induced by the activation of a cryptic splice site in intron 11, includes four intronic nucleotides upstream of exon 12, resulting in a shift in the transcript reading frame and introducing a new premature stop codon in the catalytic domain of the protein (p.Arg421SerfsTer7). The second aberrant MTM1 transcript, due to the lack of recognition of the 3′ acceptor splice site of intron 11 from the spliceosome complex, leads to the complete skipping of exon 12. We expanded the genotypic spectrum of XLMTM underlying the importance of intron–exons boundaries sequencing in male patients affected by XLMTM.
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spelling pubmed-94993152022-09-23 Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy Bosco, Luca Leone, Daniela Costa Comellas, Laura Monforte, Mauro Pane, Marika Mercuri, Eugenio Bertini, Enrico D’Amico, Adele Fattori, Fabiana Int J Mol Sci Case Report X-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the novel hemizygous MTM1 c.1261-5T>G intronic variant, which interferes with the normal splicing process, generating two different abnormal transcripts simultaneously expressed in the patient’s muscular cells. The first aberrant transcript, induced by the activation of a cryptic splice site in intron 11, includes four intronic nucleotides upstream of exon 12, resulting in a shift in the transcript reading frame and introducing a new premature stop codon in the catalytic domain of the protein (p.Arg421SerfsTer7). The second aberrant MTM1 transcript, due to the lack of recognition of the 3′ acceptor splice site of intron 11 from the spliceosome complex, leads to the complete skipping of exon 12. We expanded the genotypic spectrum of XLMTM underlying the importance of intron–exons boundaries sequencing in male patients affected by XLMTM. MDPI 2022-09-07 /pmc/articles/PMC9499315/ /pubmed/36142184 http://dx.doi.org/10.3390/ijms231810274 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Bosco, Luca
Leone, Daniela
Costa Comellas, Laura
Monforte, Mauro
Pane, Marika
Mercuri, Eugenio
Bertini, Enrico
D’Amico, Adele
Fattori, Fabiana
Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy
title Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy
title_full Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy
title_fullStr Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy
title_full_unstemmed Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy
title_short Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy
title_sort novel splicing mutation in mtm1 leading to two abnormal transcripts causes severe myotubular myopathy
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499315/
https://www.ncbi.nlm.nih.gov/pubmed/36142184
http://dx.doi.org/10.3390/ijms231810274
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