Key result
Recessive DNAJB4 variants linked to myopathy, with J-domain missense mutations carrying ~75% mortality.
Why the study?
Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, but the broader clinical and genetic spectrum is not well characterized.
Observational (n=7)
Yes
DNAJB4 is an emerging cause of myopathy with rigid spine syndrome, where J-domain missense variants predict a more severe phenotype.
Answers are grounded in this paper and cite their sources.
May support DNAJB4 testing in rigid-spine myopathy with respiratory failure; leaves open validation of J-domain severity in larger cohorts.
Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.
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Inoue et al. (2024) conducted an observational in DNAJB4 myopathy (n=7). DNAJB4 pathogenic variants vs. Other DNAJB4 variants (for genotype-phenotype correlation) was evaluated on Genotype-phenotype correlation (disease severity and age of onset). Recessive DNAJB4 variants cause myopathy with early respiratory failure and rigid spine syndrome, with J-domain missense variants associated with earlier onset (0.5 vs 28 years, p=0.035) and higher mortality (75% vs 14%, p=0.046).
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