A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy

Acta Neuropathol Commun. 2021 Feb 8;9(1):23. doi: 10.1186/s40478-020-01046-w.

Abstract

Mutations in the DNAJB6 gene have been identified as rare causes of myofibrillar myopathies. However, the underlying pathophysiologica mechanisms remain elusive. DNAJB6 has two known isoforms, including the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, which was thought to be the pathogenic isoform. Here, we report a novel recessive mutation c.695_699del (p. Val 232 Gly fs*7) in the DNAJB6 gene, associated with an apparently recessively inherited late onset distal myofibrillar myopathy in a Chinese family. Notably, the novel mutation localizes to exon 9 and uniquely encodes DNAJB6a. We further identified that this mutation decreases the mRNA and protein levels of DNAJB6a and results in an age-dependent recessive toxic effect on skeletal muscle in knock-in mice. Moreover, the mutant DNAJB6a showed a dose-dependent anti-aggregation effect on polyglutamine-containing proteins in vitro. Taking together, these findings reveal the pathogenic role of DNAJB6a insufficiency in myofibrillar myopathies and expand upon the molecular spectrum of DNAJB6 mutations.

Keywords: DNAJB6a; Homozygous mutation; Human; Mice; Myofibrillar myopathy; Novel.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Asian People
  • Distal Myopathies / diagnostic imaging
  • Distal Myopathies / genetics*
  • Distal Myopathies / pathology
  • Distal Myopathies / physiopathology
  • Gene Knock-In Techniques
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / genetics*
  • HSP40 Heat-Shock Proteins / metabolism
  • HSP40 Heat-Shock Proteins / physiology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Molecular Chaperones / physiology
  • Muscle, Skeletal / pathology*
  • Muscle, Skeletal / physiopathology*
  • Mutation*
  • Myopathies, Structural, Congenital / diagnostic imaging
  • Myopathies, Structural, Congenital / genetics*
  • Myopathies, Structural, Congenital / pathology
  • Myopathies, Structural, Congenital / physiopathology
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology
  • Phenotype

Substances

  • DNAJB6 protein, human
  • HSP40 Heat-Shock Proteins
  • Molecular Chaperones
  • Nerve Tissue Proteins

Supplementary concepts

  • Myofibrillar Myopathy