Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations
Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations
复制标题
DOI：
10.1002/humu.23189
复制
发表时间：
2017-05-01
期刊：
影响因子：
3.9
通讯作者：
Stojkovic, Tanya
中科院分区：
文献类型：
--
作者：
Echaniz-Laguna, Andoni;Geuens, Thomas;Stojkovic, Tanya
在这项研究中，我们描述了远端遗传性运动神经病的表型谱引起的突变的小热休克蛋白HSPB 1和HSPB 8和新发现的变体的功能后果进行调查。在510例远端运动神经病变的无关患者中，我们确定了HSPB 1（28例索引患者/510; 5.5%）和HSPB 8（4例索引患者/510; 0.8%）基因的突变。患者有缓慢进展的下肢远端（100%）和近端（13%）无力（100%），轻度下肢感觉受累（31%），足部畸形（73%），进行性上肢远端无力（29%），血清肌酸激酶水平轻度升高（100%），中枢神经系统受累（9%）。我们鉴定了12个HSPB 1和4个HSPB 8突变，包括5个和3个以前未报道的突变。传播是显性的（78%），隐性的（3%），或从头（19%）。HSPB 1中的三个错义突变（Pro7 Ser、Gly 53 Asp和Gln 128 Arg）引起神经丝的过度磷酸化，而C-末端突变Ser 187 Leu触发蛋白质聚集。两个移码突变（Leu 58 fs和Ala 61 fs）产生一个提前终止密码子，导致蛋白酶体降解。HSPB 8中的两个突变（Lys 141 Met/Asn）表现出与Bag 3的结合增加。我们证明HSPB 1和HSPB 8突变是遗传性运动轴索神经病的主要原因。突变导致不同的功能结果，进一步证明了小的热休克蛋白的多效性。(C)2017 Wiley Periodicals，Inc.
In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C-terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins. (C) 2017 Wiley Periodicals, Inc.