A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Mutations in the DNAJB6 gene are rare causes of myofibrillar myopathies, but the exact mechanisms are unclear.
• DNAJB6 has nuclear (DNAJB6a) and cytoplasmic (DNAJB6b) isoforms, with DNAJB6b previously considered the primary pathogenic form.

Observation:

• A novel recessive mutation (c.695_699del) in DNAJB6 was identified in a Chinese family with late-onset distal myofibrillar myopathy.
• This mutation uniquely affects exon 9, specifically impacting the DNAJB6a isoform.

Findings:

• The mutation reduces DNAJB6a mRNA and protein levels.
• Knock-in mice models demonstrated an age-dependent, recessive toxic effect of the mutation on skeletal muscle.
• Mutant DNAJB6a exhibited a dose-dependent inhibition of polyglutamine protein aggregation in vitro.

Implications:

• This research highlights the critical role of DNAJB6a insufficiency in the pathogenesis of myofibrillar myopathies.
• The findings expand the known spectrum of DNAJB6 mutations associated with muscle disorders and clarify isoform-specific roles.