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 GovernaliJohann 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)1078-1095
Number of pages18
JournalAmerican journal of human genetics
Volume107
Issue number6
DOIs
Publication statusPublished - 3 Dec 2020

Cite this