Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy
Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy
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DOI：
10.1038/ng1328
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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：
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作者：
Irobi, J;Van Impe, K;Timmerman, V
远端遗传性运动神经病是周围神经系统的纯运动障碍，导致远端肢体肌肉的严重萎缩和消耗。在两个与染色体12q24.3连锁的远端遗传性运动神经病II型家系中，我们在小热休克22-kDa蛋白8（由HSPB 8编码;也称为HSP 22）中发现了相同的突变（K141 N）。我们在两个较小的家族中发现了第二个突变（K141 E）。两种突变都针对相同的氨基酸，这对小热休克蛋白α A-晶状体蛋白的结构和功能完整性至关重要（2）。这种带正电荷的残基，当在其他小的热休克蛋白中发生突变时，会导致各种人类疾病。（3，4）免疫共沉淀实验显示两种HSPB 8突变体与相互作用伴侣HSPB 1的结合更强。突变型HSPB 8在培养细胞中的表达促进了细胞内聚集体的形成。我们的研究结果提供了进一步的证据，热休克蛋白的突变在神经退行性疾病中具有重要作用。
Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles'. In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). We found a second mutation (K141E) in two smaller families. Both mutations target the same amino acid, which is essential to the structural and functional integrity of the small heat-shock protein alphaA-crystallin(2). This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders(.)(3,4) Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1. Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat-shock proteins have an important role in neurodegenerative disorders.