| Literature DB >> 33217308 |
Sandra Donkervoort1, Carl E Kutzner2, Ying Hu1, Xavière Lornage3, John Rendu4, Tanya Stojkovic5, Jonathan Baets6, Sarah B Neuhaus1, Jantima Tanboon7, Reza Maroofian8, Véronique Bolduc1, Magdalena Mroczek9, Stefan Conijn10, Nancy L Kuntz11, Ana Töpf9, Soledad Monges12, Fabiana Lubieniecki12, Riley M McCarty1, Katherine R Chao13, Serena Governali10, Johann Böhm3, Kanokwan Boonyapisit14, Edoardo Malfatti15, Tumtip Sangruchi16, Iren Horkayne-Szakaly17, Carola Hedberg-Oldfors18, Stephanie Efthymiou8, Satoru Noguchi19, Sarah Djeddi3, Aritoshi Iida20, Gabriella di Rosa21, Chiara Fiorillo22, Vincenzo Salpietro22, Niklas Darin23, Julien Fauré4, Henry Houlden8, Anders Oldfors18, Ichizo Nishino24, Willem de Ridder6, Volker Straub25, Wojciech Pokrzywa26, Jocelyn Laporte3, A Reghan Foley1, Norma B Romero27, Coen Ottenheijm28, Thorsten Hoppe29, Carsten G Bönnemann30.
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.Entities:
Keywords: C. elegans; UNC-45; UNC45B; chaperone; core myopathy; muscle; myofibrillar; myosin; sarcomere
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Year: 2020 PMID： 33217308 PMCID： PMC7820787 DOI： 10.1016/j.ajhg.2020.11.002
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025