@article{1827a41e095641ea936c3edb965ff402,
title = "Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores",
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.",
keywords = "C. elegans, UNC-45, UNC45B, chaperone, core myopathy, muscle, myofibrillar, myosin, sarcomere",
author = "Sandra Donkervoort and Kutzner, {Carl E.} and Ying Hu and Xavi{\`e}re Lornage and John Rendu and Tanya Stojkovic and Jonathan Baets and Neuhaus, {Sarah B.} and Jantima Tanboon and Reza Maroofian and V{\'e}ronique Bolduc and Magdalena Mroczek and Stefan Conijn and Kuntz, {Nancy L.} and Ana T{\"o}pf and Soledad Monges and Fabiana Lubieniecki and McCarty, {Riley M.} and Chao, {Katherine R.} and Serena Governali and Johann B{\"o}hm and Kanokwan Boonyapisit and Edoardo Malfatti and Tumtip Sangruchi and Iren Horkayne-Szakaly and Carola Hedberg-Oldfors and Stephanie Efthymiou and Satoru Noguchi and Sarah Djeddi and Aritoshi Iida and {di Rosa}, Gabriella and Chiara Fiorillo and Vincenzo Salpietro and Niklas Darin and Julien Faur{\'e} and Henry Houlden and Anders Oldfors and Ichizo Nishino and {de Ridder}, Willem and Volker Straub and Wojciech Pokrzywa and Jocelyn Laporte and Foley, {A. Reghan} and Romero, {Norma B.} and Coen Ottenheijm and Thorsten Hoppe and B{\"o}nnemann, {Carsten G.}",
note = "Funding Information: We thank the individuals and their families for participating in our research study and Christopher Mendoza, Christine Jones, Gilberto (“Mike”) Averion, Rupleen Kaur, Kia Brooks, and Janelle Geist Hauserman for their help in the clinic and the laboratory. We would like to thank the CHUGA Molecular Biology facility platform for their help with exome sequencing. We thank Y. Kohara, the Caenorhabditis Genetics Center (funded by the NIH National Center for Research Resources), the Dana-Farber Cancer Institute, and Addgene and Geneservice for plasmids, cDNAs, and worm strains. We thank the CECAD Imaging facility for support with confocal microscopy. In particular, we thank Vishnu Balaji for the purification of LET-70-HIS and VSV-CHN-1-HIS proteins and help with in vitro studies. For the complete Acknowledgments including funding sources, please see Supplemental Information. Funding Information: We thank the individuals and their families for participating in our research study and Christopher Mendoza, Christine Jones, Gilberto (“Mike”) Averion, Rupleen Kaur, Kia Brooks, and Janelle Geist Hauserman for their help in the clinic and the laboratory. We would like to thank the CHUGA Molecular Biology facility platform for their help with exome sequencing. We thank Y. Kohara, the Caenorhabditis Genetics Center (funded by the NIH National Center for Research Resources), the Dana-Farber Cancer Institute, and Addgene and Geneservice for plasmids, cDNAs, and worm strains. We thank the CECAD Imaging facility for support with confocal microscopy. In particular, we thank Vishnu Balaji for the purification of LET-70-HIS and VSV-CHN-1-HIS proteins and help with in vitro studies. For the complete Acknowledgments including funding sources, please see Supplemental Information . Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = dec,
day = "3",
doi = "10.1016/j.ajhg.2020.11.002",
language = "English (US)",
volume = "107",
pages = "1078--1095",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",
}