Mutations in the J domain of DNAJB6 cause dominant distal myopathy.
Mutations in the J domain of DNAJB6 cause dominant distal myopathy.
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DOI：
10.1016/j.nmd.2019.11.005
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发表时间：
2020-01
影响因子：
2.8
通讯作者：
Udd, Bjarne
中科院分区：
文献类型：
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作者：
Palmio, Johanna;Jonson, Per Harald;Inoue, Michio;Sarparanta, Jaakko;Bengoechea, Rocio;Savarese, Marco;Vihola, Anna;Jokela, Manu;Nakagawa, Masanori;Noguchi, Satoru;Olive, Montse;Masingue, Marion;Kerty, Emilia;Hackman, Peter;Weihl, Conrad C.;Nishino, Ichizo;Udd, Bjarne
来自5个家庭的8例未确诊的显性远端肌病患者接受了临床、神经生理和肌肉活检检查。分子遗传学研究使用所有已知肌病基因的靶向测序，然后使用Sanger测序分离受影响家族的已鉴定突变。DNAJB6 J结构域的两个新突变C . 149c >T （p.A50V）和C . 161a >C （p.E54A）被确定为疾病的病因。p.A50V受累的肌肉以小腿远端为主，而p.E54A受累的肌肉更接近远端。组织学结果与先前报道的DNAJB6肌病相似。与报道的DNAJB6的甘氨酸/苯丙氨酸（G/F）结构域的致病突变一致，通过过滤陷阱试验和TDP-43解聚试验，这两个新突变都显示出抗聚集能力降低。蛋白质的建模显示突变残基与G/F结构域非常接近。DNAJB6引起肌病的突变不仅位于G/F结构域，而且位于J结构域。鉴定的J结构域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。
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.
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影响因子：
4
作者：
Nishikawa, Atsuko;Mitsuhashi, Satomi;Nishino, Ichizo
通讯作者：
Nishino, Ichizo
影响因子：
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作者：
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通讯作者：
Nigro V
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Nishino, Ichizo
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通讯作者：
Kampinga, Harm H.
影响因子：
14.8
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通讯作者：
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