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Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.

Donkervoort, S; Kutzner, CE; Hu, Y; Lornage, X; Rendu, J; Stojkovic, T; Baets, J; Neuhaus, SB; Tanboon, J; Maroofian, R; et al. Donkervoort, S; Kutzner, CE; Hu, Y; Lornage, X; Rendu, J; Stojkovic, T; Baets, J; Neuhaus, SB; Tanboon, J; Maroofian, R; Bolduc, V; Mroczek, M; Conijn, S; Kuntz, NL; Töpf, A; Monges, S; Lubieniecki, F; McCarty, RM; Chao, KR; Governali, S; Böhm, J; Boonyapisit, K; Malfatti, E; Sangruchi, T; Horkayne-Szakaly, I; Hedberg-Oldfors, C; Efthymiou, S; Noguchi, S; Djeddi, S; Iida, A; di Rosa, G; Fiorillo, C; Salpietro, V; Darin, N; Fauré, J; Houlden, H; Oldfors, A; Nishino, I; de Ridder, W; Straub, V; Pokrzywa, W; Laporte, J; Foley, AR; Romero, NB; Ottenheijm, C; Hoppe, T; Bönnemann, CG (2020) Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores. Am J Hum Genet, 107 (6). pp. 1078-1095. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2020.11.002
SGUL Authors: Maroofian, Reza

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Abstract

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.

Item Type: Article
Additional Information: © 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: C. elegans, UNC-45, UNC45B, chaperone, core myopathy, muscle, myofibrillar, myosin, sarcomere, Adolescent, Adult, Alleles, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Female, Genetic Variation, Humans, Loss of Function Mutation, Male, Molecular Chaperones, Muscle, Skeletal, Muscular Diseases, Mutation, Missense, Myofibrils, Myosins, Sarcomeres, Sequence Analysis, RNA, Transgenes, Whole Exome Sequencing, Young Adult, Myofibrils, Sarcomeres, Muscle, Skeletal, Animals, Humans, Caenorhabditis elegans, Muscular Diseases, Myosins, Caenorhabditis elegans Proteins, Molecular Chaperones, Sequence Analysis, RNA, Mutation, Missense, Alleles, Transgenes, Adolescent, Adult, Female, Male, Genetic Variation, Young Adult, Whole Exome Sequencing, Loss of Function Mutation, C. elegans, UNC-45, UNC45B, chaperone, core myopathy, muscle, myofibrillar, myosin, sarcomere, 06 Biological Sciences, 11 Medical and Health Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
3 December 2020Published
19 November 2020Published Online
3 November 2020Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
PubMed ID: 33217308
Web of Science ID: WOS:000596042000005
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113886
Publisher's version: https://doi.org/10.1016/j.ajhg.2020.11.002

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