A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy

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.

Case Report: A Novel Splice-Site Mutation in DNAJB6 Associated With Juvenile-Onset Proximal–Distal Myopathy in a Chinese Patient

“…In addition, it has been known that LGMD1D was autosomal-dominantly inherited myopathy caused by gain-of-deleterious-function mutations in the DNAJB6 gene, and DNAJB6b was known as the pathogenic isoform. Interestingly, however, a homozygous mutation (p.Val232Gly fs*7) that localized to exon 9 of the DNAJB6 gene was reported to cause an autosomal-recessively inherited late-onset very recently ( Qian et al, 2021 ). The novel mutation exclusively caused loss of the “a” region in DNAJB6a and resulted in a recessive toxic effect.…”

DNAJB6 Isoform Specific Knockdown: Therapeutic Potential for LGMDD1

“…13 However, a patient with a myofibrillar myopathy was recently reported to have homozygous recessive frameshift mutations selectively affecting the DNAJB6a isoform, resulting in loss of A isoform protein expression. 6 These findings raise concern about the safety of any intervention that greatly reduces DNAJB6a levels. We occasionally noticed an increase in DNAJB6a levels following treatment with BPAS (Fig 1C , 1J, 3C).…”

“…30 MS1 scans were acquired in the Orbitrap at 120 k resolution with a scan range of 350–1800 m/z. The AGC target was 1×10 6 , and the maximum injection time was 50 ms. MS2 scans were acquired with higher-energy collisional dissociation (HCD) activation type in the Orbitrap at 50 k resolution with the defined first mass 110 m/z. The isolation window was 0.5 m/z, collision energy was 38%, maximum injection time was dynamic, and AGC target was standard.…”

“…4 However, there is some evidence suggesting DNAJB6a is not completely dispensable in muscle, as a patient with a myofibrillar myopathy was found to have recessively inherited truncating frameshift mutations selectively affecting DNAJB6a. 6 Overall, each isoform’s role in muscle and their contribution to LGMDD1 pathogenesis remains unclear. Additionally, there is mixed evidence whether disease pathogenesis occurs via a dominant negative effect, a toxic gain of function, or possibly a combination of both.4,5,7–11…”

Clinical and genetic analysis of five children with ornithine transcarbamylase deficiency: two novel mutations

“…Then, the data would be transformed to VCF format. Variants were further annotated by ANNOVAR software (http://annovar.openbioinformatics.org/en/latest/), and associated with multiple databases, such as, 1000 genome, ESP6500, dbSNP, EXAC, Inhouse (MyGenostics), HGMD, and also predicted by SIFT, PolyPhen-2, MutationTaster and GERP++ [11,12].…”