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Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4

Michio Inoue1,2,3, Satoru Noguchi4,5, Yukiko U Inoue6

  • 1Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.

Acta Neuropathologica
|December 13, 2022
PubMed

Insights

A DNAJB4 gene variant causes a dominant distal myopathy by impairing chaperone function, leading to muscle weakness and specific protein aggregates in muscle fibers. This study highlights DNAJB4

Area of Science:

  • Molecular Biology
  • Genetics
  • Neurology

Background:

  • DnaJ homolog, subfamily B, member 4 (DNAJB4) is a heat shock protein 40 chaperone highly expressed in myofibers.
  • Chaperonopathies, disorders caused by defective chaperone proteins, can lead to various myopathies.

Purpose of the Study:

  • To investigate the genetic basis and molecular mechanisms of a dominantly inherited distal myopathy.
  • To determine the role of DNAJB4 in skeletal muscle proteostasis and disease pathogenesis.

Main Methods:

  • Genetic analysis to identify variants in DNAJB4 in affected families.
  • Creation and analysis of Dnajb4F90L knockin and knockout mouse models.
  • Muscle pathology assessment, including protein accumulation and fiber type specificity.

Main Results:

  • A heterozygous c.270 T>A (p.F90L) variant in DNAJB4 was identified in a family with distal myopathy.
  • Affected individuals exhibited cytoplasmic inclusions and accumulation of desmin, p62, HSP70, and DNAJB4 in type 1 fibers.
  • Dnajb4F90L knockin and knockout mice showed muscle weakness and soleus muscle pathology mirroring human findings.

Conclusions:

  • The identified DNAJB4 variant is causative for dominant distal myopathy, leading to defective chaperone function.
  • DNAJB4 plays a critical role in skeletal muscle proteostasis, and its dysfunction results in selective muscle degeneration.
  • This study identifies a novel DNAJB4-associated chaperonopathy affecting skeletal muscle.

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