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Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy
Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower’s sign, and skeletal muscle biops...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921565/ https://www.ncbi.nlm.nih.gov/pubmed/31852522 http://dx.doi.org/10.1186/s40478-019-0869-1 |
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author | Dafsari, Hormos Salimi Kocaturk, Nur Mehpare Daimagüler, Hülya-Sevcan Brunn, Anna Dötsch, Jörg Weis, Joachim Deckert, Martina Cirak, Sebahattin |
author_facet | Dafsari, Hormos Salimi Kocaturk, Nur Mehpare Daimagüler, Hülya-Sevcan Brunn, Anna Dötsch, Jörg Weis, Joachim Deckert, Martina Cirak, Sebahattin |
author_sort | Dafsari, Hormos Salimi |
collection | PubMed |
description | Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower’s sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a “template” defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown–models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity. |
format | Online Article Text |
id | pubmed-6921565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69215652019-12-30 Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy Dafsari, Hormos Salimi Kocaturk, Nur Mehpare Daimagüler, Hülya-Sevcan Brunn, Anna Dötsch, Jörg Weis, Joachim Deckert, Martina Cirak, Sebahattin Acta Neuropathol Commun Case Report Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower’s sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a “template” defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown–models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity. BioMed Central 2019-12-18 /pmc/articles/PMC6921565/ /pubmed/31852522 http://dx.doi.org/10.1186/s40478-019-0869-1 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Case Report Dafsari, Hormos Salimi Kocaturk, Nur Mehpare Daimagüler, Hülya-Sevcan Brunn, Anna Dötsch, Jörg Weis, Joachim Deckert, Martina Cirak, Sebahattin Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy |
title | Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy |
title_full | Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy |
title_fullStr | Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy |
title_full_unstemmed | Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy |
title_short | Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy |
title_sort | bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone b are a cause for congenital myopathy |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921565/ https://www.ncbi.nlm.nih.gov/pubmed/31852522 http://dx.doi.org/10.1186/s40478-019-0869-1 |
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