Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases.

中文翻译：

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DNAJB6 的 J 域突变导致显性远端肌病

来自 5 个家族的 8 名患有未确诊的显性远端肌病的患者接受了临床、神经生理学和肌肉活检检查。使用所有已知肌病基因的靶向测序进行分子遗传学研究，然后使用 Sanger 测序分离受影响家族中已识别的突变。DNAJB6 J 结构域中的两个新突变 c.149C>T (p.A50V) 和 c.161A>C (p.E54A) 被确定为疾病的原因。p.A50V 的肌肉受累以小腿远端为主，而 p.E54A 的受累更接近-远端。组织学发现与先前在 DNAJB6 肌病中报道的相似。与报道的 DNAJB6 甘氨酸/苯丙氨酸 (G/F) 结构域致病突变一致，通过过滤陷阱测定和 TDP-43 解聚测定，这两种新突变均显示抗聚集能力降低。蛋白质建模显示突变残基与 G/F 结构域非常接近。DNAJB6 中的肌病致病突变不仅位于 G/F 结构域，还位于 J 结构域。J 结构域中确定的突变导致显性远端和近端-远端肌病，证实在远端肌病病例中应考虑 DNAJB6 突变。