Sandra DonkervoortCarl E. KutznerYing HuXavière LornageJohn RenduTanya StojkovicJonathan BaetsSarah B. NeuhausJantima TanboonReza MaroofianVéronique BolducMagdalena MroczekStefan ConijnNancy L. KuntzAna TöpfSoledad MongesFabiana LubienieckiRiley M. McCartyKatherine R. ChaoSerena GovernaliJohann BöhmKanokwan BoonyapisitEdoardo MalfattiTumtip SangruchiIren Horkayne-SzakalyCarola Hedberg-OldforsStephanie EfthymiouSatoru NoguchiSarah DjeddiAritoshi IidaGabriella di RosaChiara FiorilloVincenzo SalpietroNiklas DarinJulien FauréHenry HouldenAnders OldforsIchizo NishinoWillem de RidderVolker StraubWojciech PokrzywaJocelyn LaporteA. Reghan FoleyNorma B. RomeroCoen OttenheijmThorsten HoppeCarsten G. BönnemannUniversite Grenoble AlpesUniversité de StrasbourgInternational Institute of Molecular and Cell BiologyInstituut Born-BungeGöteborg University, Sahlgrenska AcademyUniversity of Newcastle upon Tyne, Faculty of Medical SciencesUniversità degli Studi di GenovaUniversity of CologneNational Institute of Neuroscience, KodairaUCL Queen Square Institute of NeurologyNational Center of Neurology and Psychiatry KodairaIRCCS Istituto Giannina Gaslini - Ospedale PediatricoNational Institute of Neurological Disorders and Stroke (NINDS)Hopital Raymond PoincareUniversitair Ziekenhuis AntwerpenNorthwestern University Feinberg School of MedicineUniversiteit AntwerpenUniversità degli Studi di MessinaFaculty of Medicine, Siriraj Hospital, Mahidol UniversityThe University of ArizonaCentre Hospitalier Universitaire de GrenobleAmsterdam UMC - Vrije Universiteit AmsterdamFundacion Hospital de Pediatria Professor Dr. Juan P. GarrahanSorbonne UniversiteThe Newcastle Upon Tyne Hospitals NHS Foundation TrustBroad InstituteDefense Health AgencyInstitute of Myology2020-12-282020-12-282020-12-03American Journal of Human Genetics. Vol.107, No.6 (2020), 1078-109515376605000292972-s2.0-85097368013https://repository.li.mahidol.ac.th/handle/20.500.14594/60384© 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1016/j.ajhg.2020.11.002