小热休克蛋白22中的热点残基导致远端运动神经病。

Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.

作者信息

Irobi Joy, Van Impe Katrien, Seeman Pavel, Jordanova Albena, Dierick Ines, Verpoorten Nathalie, Michalik Andrej, De Vriendt Els, Jacobs An, Van Gerwen Veerle, Vennekens Krist'l, Mazanec Radim, Tournev Ivailo, Hilton-Jones David, Talbot Kevin, Kremensky Ivo, Van Den Bosch Ludo, Robberecht Wim, Van Vandekerckhove Joël, Van Broeckhoven Christine, Gettemans Jan, De Jonghe Peter, Timmerman Vincent

机构信息

Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium.

出版信息

Nat Genet. 2004 Jun;36(6):597-601. doi: 10.1038/ng1328. Epub 2004 May 2.

DOI:10.1038/ng1328

PMID:15122253

Abstract

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. This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders. 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.

摘要

远端遗传性运动神经病是一种周围神经系统的纯运动性疾病，可导致远端肢体肌肉严重萎缩和消瘦。在两个与12q24.3染色体连锁的II型远端遗传性运动神经病家系中，我们在小热休克22 kDa蛋白8（由HSPB8编码；也称为HSP22）中鉴定出相同的突变（K141N）。我们在两个较小的家族中发现了第二个突变（K141E）。这两个突变靶向同一个氨基酸，该氨基酸对小热休克蛋白αA-晶状体蛋白的结构和功能完整性至关重要。这个带正电荷的残基在其他小热休克蛋白中发生突变时，会导致各种人类疾病。免疫共沉淀实验表明，两种HSPB8突变体与相互作用伴侣HSPB1的结合更强。突变型HSPB8在培养细胞中的表达促进了细胞内聚集体的形成。我们的研究结果进一步证明，热休克蛋白的突变在神经退行性疾病中起重要作用。