A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy.
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.
['Qian|Fang-Yuan|FY|', 'Guo|Yu-Dong|YD|', 'Zu|Juan|J|', 'Zhang|Jin-Hua|JH|', 'Zheng|Yi-Ming|YM|', 'Abdoulaye|Idriss Ali|IA|', 'Pan|Zhao-Hui|ZH|', 'Xie|Chun-Ming|CM|', 'Gao|Han-Chao|HC|', 'Zhang|Zhi-Jun|ZJ|']
D000368:Aged D000818:Animals D044466:Asians D049310:Distal Myopathies D055879:Gene Knock-In Techniques D057809:HEK293 Cells D050956:HSP40 Heat-Shock Proteins D006801:Humans D008297:Male D051379:Mice D008822:Mice, Transgenic D018832:Molecular Chaperones D018482:Muscle, Skeletal D009154:Mutation D020914:Myopathies, Structural, Congenital D009419:Nerve Tissue Proteins D010641:Phenotype
Novel DNAJB6a Myofibrillar myopathy Mice Homozygous mutation Human