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Title
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Pathogenic variants in the myosin chaperone UNC-45B cause progressive myopathy with eccentric cores
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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The American journal of human genetics / American Society of Human Genetics [Bethesda, Md] - New York, N.Y., 1949, currens
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Publication
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New York, N.Y.
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2020
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ISSN
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0002-9297
[print]
1537-6605
[online]
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DOI
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10.1016/J.AJHG.2020.11.002
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Volume/pages
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107
:6
(2020)
, p. 1078-1095
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ISI
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000596042000005
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Pubmed ID
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33217308
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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