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

Am J Hum Genet. 2020 Dec 3;107(6):1078-1095. doi: 10.1016/j.ajhg.2020.11.002. Epub 2020 Nov 19.

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.

Keywords: C. elegans; UNC-45; UNC45B; chaperone; core myopathy; muscle; myofibrillar; myosin; sarcomere.

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / physiology*
  • Female
  • Genetic Variation
  • Humans
  • Loss of Function Mutation
  • Male
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / physiology*
  • Muscle, Skeletal / pathology
  • Muscular Diseases / genetics*
  • Mutation, Missense*
  • Myofibrils
  • Myosins
  • Sarcomeres / metabolism
  • Sequence Analysis, RNA
  • Transgenes
  • Whole Exome Sequencing
  • Young Adult

Substances

  • Caenorhabditis elegans Proteins
  • Molecular Chaperones
  • UNC45B protein, human
  • unc-45 protein, C elegans
  • Myosins