Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy
Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy
复制标题
DOI：
10.1038/ng1354
复制
发表时间：
2004-06-01
期刊：
影响因子：
30.8
通讯作者：
Timmerman, V
中科院分区：
文献类型：
--
作者：
Evgrafov, OV;Mersiyanova, I;Timmerman, V
腓骨肌萎缩症（CMT）是最常见的遗传性神经肌肉疾病，其特征是相当大的临床和遗传异质性（1）。我们先前报道了一个俄罗斯常染色体显性轴突型CMT家系，并将该病的基因座（CMT 2F; OMIM 606595）定位于染色体7 q11-q21（参考文献2）。在此，我们报告了编码27 kDa小热休克蛋白131（HSPB 1，也称为HSP 27）的基因中的错义突变，该基因在CMT 2F家族中分离。在301名CMT患者和115名远端遗传性运动神经病（远端HMN）患者中筛查HSPB 1突变，证实了先前观察到的突变，并确定了另外4个错义突变。我们观察到额外的HSPB 1突变在四个家庭与远端HMN和一个人与CMT神经病变。四个突变位于Hsp 20-α-晶状体蛋白结构域，一个突变位于HSP 27蛋白的C-末端部分。用突变的HSPB 1转染的神经元细胞比表达野生型蛋白的细胞存活率低。神经丝轻链（NEFL）和突变型HSPB 1的共转染导致细胞内缺乏细胞质中间丝的神经丝组装改变。
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity(1). We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11-q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein 131 (HSPB1, also called HSP27) that segregates in the family with CMT2F Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20-alpha-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments.