Publication: Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
Issued Date
2020-12-03
Resource Type
ISSN
15376605
00029297
00029297
Other identifier(s)
2-s2.0-85097368013
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Mahidol University
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SCOPUS
Bibliographic Citation
American Journal of Human Genetics. Vol.107, No.6 (2020), 1078-1095
Suggested Citation
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. American Journal of Human Genetics. Vol.107, No.6 (2020), 1078-1095. doi:10.1016/j.ajhg.2020.11.002 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/60384
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Title
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
Author(s)
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
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
Other Contributor(s)
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
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
Abstract
© 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.
