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 language | English |
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Pages (from-to) | 1078-1095 |
Number of pages | 18 |
Journal | American Journal of Human Genetics |
Volume | 107 |
Issue number | 6 |
DOIs | |
Publication status | Published - Dec 3 2020 |
Keywords
- Adolescent
- Adult
- Alleles
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins/genetics
- Female
- Genetic Variation
- Humans
- Loss of Function Mutation
- Male
- Molecular Chaperones/genetics
- Muscle, Skeletal/pathology
- Muscular Diseases/genetics
- Mutation, Missense
- Myofibrils
- Myosins
- Sarcomeres/metabolism
- Sequence Analysis, RNA
- Transgenes
- Whole Exome Sequencing
- Young Adult