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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.

SUBMITTER: Donkervoort S 

PROVIDER: S-EPMC7820787 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.

Donkervoort Sandra S   Kutzner Carl E CE   Hu Ying Y   Lornage Xavière X   Rendu John J   Stojkovic Tanya T   Baets Jonathan J   Neuhaus Sarah B SB   Tanboon Jantima J   Maroofian Reza R   Bolduc Véronique V   Mroczek Magdalena M   Conijn Stefan S   Kuntz Nancy L NL   Töpf Ana A   Monges Soledad S   Lubieniecki Fabiana F   McCarty Riley M RM   Chao Katherine R KR   Governali Serena S   Böhm Johann J   Boonyapisit Kanokwan K   Malfatti Edoardo E   Sangruchi Tumtip T   Horkayne-Szakaly Iren I   Hedberg-Oldfors Carola C   Efthymiou Stephanie S   Noguchi Satoru S   Djeddi Sarah S   Iida Aritoshi A   di Rosa Gabriella G   Fiorillo Chiara C   Salpietro Vincenzo V   Darin Niklas N   Fauré Julien J   Houlden Henry H   Oldfors Anders A   Nishino Ichizo I   de Ridder Willem W   Straub Volker V   Pokrzywa Wojciech W   Laporte Jocelyn J   Foley A Reghan AR   Romero Norma B NB   Ottenheijm Coen C   Hoppe Thorsten T   Bönnemann Carsten G CG  

American journal of human genetics 20201119 6


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 localizatio  ...[more]

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