Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4
Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4
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DOI：
10.1007/s00401-022-02530-4
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发表时间：
2022-12-13
影响因子：
12.7
通讯作者：
Nishino, Ichizo
中科院分区：
文献类型：
--
作者：
Inoue, Michio;Noguchi, Satoru;Nishino, Ichizo
DNAJ同源物，B亚家族，成员4，是DNAJB4编码的热休克蛋白40分子伴侣中的一员，在肌纤维中高度表达。我们在一个以遗传性远端肌病为主的家族中发现了DNAJB4基因的杂合子c.270T>；A(p.F90L)变异，在该家族中，受影响的成员在肌肉病理上具有特殊的特征，表现为胞浆内包涵体的存在以及主要在1型纤维中结蛋白、p62、HSP70和DNAJB4的积聚。DNAJB4F90L基因敲除小鼠和DNAJB4F90L基因敲除小鼠都出现了肌肉无力，并在比目鱼肌中重现了患者的肌肉病理，DNAJB4在比目鱼肌中表达最高。这些数据表明，已识别的变异是致病的，导致特定肌肉纤维中的伴侣功能缺陷和选择性肌肉变性。这项研究通过确定相关的伴侣病，证明了DNAJB4在骨骼肌蛋白平衡中的重要性。
DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers. Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative, resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.