Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
© 2020 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-o...
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th-mahidol.603842020-12-28T13:01:00Z Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores Sandra Donkervoort Carl E. Kutzner Ying Hu Xavière Lornage John Rendu Tanya Stojkovic Jonathan Baets Sarah B. Neuhaus Jantima Tanboon Reza Maroofian Véronique Bolduc Magdalena Mroczek Stefan Conijn Nancy L. Kuntz Ana Töpf Soledad Monges Fabiana Lubieniecki Riley M. McCarty Katherine R. Chao Serena Governali Johann Böhm Kanokwan Boonyapisit Edoardo Malfatti Tumtip Sangruchi Iren Horkayne-Szakaly Carola Hedberg-Oldfors Stephanie Efthymiou Satoru Noguchi Sarah Djeddi Aritoshi Iida Gabriella di Rosa Chiara Fiorillo Vincenzo Salpietro Niklas Darin Julien Fauré Henry Houlden Anders Oldfors Ichizo Nishino Willem de Ridder Volker Straub Wojciech Pokrzywa Jocelyn Laporte A. Reghan Foley Norma B. Romero Coen Ottenheijm Thorsten Hoppe Carsten G. Bönnemann Universite Grenoble Alpes Université de Strasbourg International Institute of Molecular and Cell Biology Instituut Born-Bunge Göteborg University, Sahlgrenska Academy University of Newcastle upon Tyne, Faculty of Medical Sciences Università degli Studi di Genova University of Cologne National Institute of Neuroscience, Kodaira UCL Queen Square Institute of Neurology National Center of Neurology and Psychiatry Kodaira IRCCS Istituto Giannina Gaslini - Ospedale Pediatrico National Institute of Neurological Disorders and Stroke (NINDS) Hopital Raymond Poincare Universitair Ziekenhuis Antwerpen Northwestern University Feinberg School of Medicine Universiteit Antwerpen Università degli Studi di Messina Faculty of Medicine, Siriraj Hospital, Mahidol University The University of Arizona Centre Hospitalier Universitaire de Grenoble Amsterdam UMC - Vrije Universiteit Amsterdam Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan Sorbonne Universite The Newcastle Upon Tyne Hospitals NHS Foundation Trust Broad Institute Defense Health Agency Institute of Myology Biochemistry, Genetics and Molecular Biology Medicine © 2020 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. 2020-12-28T04:01:26Z 2020-12-28T04:01:26Z 2020-12-03 Article American Journal of Human Genetics. Vol.107, No.6 (2020), 1078-1095 10.1016/j.ajhg.2020.11.002 15376605 00029297 2-s2.0-85097368013 https://repository.li.mahidol.ac.th/handle/123456789/60384 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85097368013&origin=inward |
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Biochemistry, Genetics and Molecular Biology Medicine Sandra Donkervoort Carl E. Kutzner Ying Hu Xavière Lornage John Rendu Tanya Stojkovic Jonathan Baets Sarah B. Neuhaus Jantima Tanboon Reza Maroofian Véronique Bolduc Magdalena Mroczek Stefan Conijn Nancy L. Kuntz Ana Töpf Soledad Monges Fabiana Lubieniecki Riley M. McCarty Katherine R. Chao Serena Governali Johann Böhm Kanokwan Boonyapisit Edoardo Malfatti Tumtip Sangruchi Iren Horkayne-Szakaly Carola Hedberg-Oldfors Stephanie Efthymiou Satoru Noguchi Sarah Djeddi Aritoshi Iida Gabriella di Rosa Chiara Fiorillo Vincenzo Salpietro Niklas Darin Julien Fauré Henry Houlden Anders Oldfors Ichizo Nishino Willem de Ridder Volker Straub Wojciech Pokrzywa Jocelyn Laporte A. Reghan Foley Norma B. Romero Coen Ottenheijm Thorsten Hoppe Carsten G. Bönnemann Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores |
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© 2020 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. |
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Universite Grenoble Alpes |
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Universite Grenoble Alpes Sandra Donkervoort Carl E. Kutzner Ying Hu Xavière Lornage John Rendu Tanya Stojkovic Jonathan Baets Sarah B. Neuhaus Jantima Tanboon Reza Maroofian Véronique Bolduc Magdalena Mroczek Stefan Conijn Nancy L. Kuntz Ana Töpf Soledad Monges Fabiana Lubieniecki Riley M. McCarty Katherine R. Chao Serena Governali Johann Böhm Kanokwan Boonyapisit Edoardo Malfatti Tumtip Sangruchi Iren Horkayne-Szakaly Carola Hedberg-Oldfors Stephanie Efthymiou Satoru Noguchi Sarah Djeddi Aritoshi Iida Gabriella di Rosa Chiara Fiorillo Vincenzo Salpietro Niklas Darin Julien Fauré Henry Houlden Anders Oldfors Ichizo Nishino Willem de Ridder Volker Straub Wojciech Pokrzywa Jocelyn Laporte A. Reghan Foley Norma B. Romero Coen Ottenheijm Thorsten Hoppe Carsten G. Bönnemann |
format |
Article |
author |
Sandra Donkervoort Carl E. Kutzner Ying Hu Xavière Lornage John Rendu Tanya Stojkovic Jonathan Baets Sarah B. Neuhaus Jantima Tanboon Reza Maroofian Véronique Bolduc Magdalena Mroczek Stefan Conijn Nancy L. Kuntz Ana Töpf Soledad Monges Fabiana Lubieniecki Riley M. McCarty Katherine R. Chao Serena Governali Johann Böhm Kanokwan Boonyapisit Edoardo Malfatti Tumtip Sangruchi Iren Horkayne-Szakaly Carola Hedberg-Oldfors Stephanie Efthymiou Satoru Noguchi Sarah Djeddi Aritoshi Iida Gabriella di Rosa Chiara Fiorillo Vincenzo Salpietro Niklas Darin Julien Fauré Henry Houlden Anders Oldfors Ichizo Nishino Willem de Ridder Volker Straub Wojciech Pokrzywa Jocelyn Laporte A. Reghan Foley Norma B. Romero Coen Ottenheijm Thorsten Hoppe Carsten G. Bönnemann |
author_sort |
Sandra Donkervoort |
title |
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores |
title_short |
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores |
title_full |
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores |
title_fullStr |
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores |
title_full_unstemmed |
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores |
title_sort |
pathogenic variants in the myosin chaperone unc-45b cause progressive myopathy with eccentric cores |
publishDate |
2020 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/60384 |
_version_ |
1763490121764569088 |