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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.

SUBMITTER: Qian FY 

PROVIDER: S-EPMC7869515 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy.

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  

Acta neuropathologica communications 20210208 1


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 myo  ...[more]

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