Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease
Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease
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DOI：
10.1093/hmg/ddn003
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发表时间：
2008-04-15
影响因子：
3.5
通讯作者：
Riess, Olaf
中科院分区：
文献类型：
--
作者：
Metzger, Silke;Rong, Juan;Riess, Olaf
一种叫做亨廷顿蛋白（htt）的蛋白质中超过36个单位的多聚谷氨酰胺重复扩增是亨廷顿病（HD）的唯一已知原因。扩增的重复序列长度与发病年龄（AAO）呈负相关，然而，CAG重复序列低于60个单位的HD患者的发病年龄差异很大。除了环境因素外，不同于CAG重复序列长度扩增的遗传因素也可以改变HD的AAO。我们假设，htt相互作用的蛋白质可能有助于这种变化的AAO和研究人类htt相关蛋白-1（HAP 1）使用遗传和功能测定。我们在HAP 1基因中鉴定了六种多态性，包括一种在氨基酸441处用甲硫氨酸（M441）取代苏氨酸（T441）。分析980例欧洲HD患者，我们发现M441基因型纯合子患者的AAO延迟8年。功能测定表明，人M441-HAP 1与突变体htt的相互作用比人T441-HAP 1更紧密，减少可溶性htt降解产物，并保护免受htt介导的毒性。因此，我们提供了遗传和功能的证据，M441-HAP 1多态性修改HD的AAO。
A polyglutamine repeat expansion of more than 36 units in a protein called huntingtin (htt) is the only known cause of Huntington's disease (HD). The expanded repeat length is inversely correlated with the age-at-onset (AAO), however, the onset age among HD patients with CAG repeats below 60 units varies considerably. In addition to environmental factors, genetic factors different from the expanded CAG repeat length can modify the AAO of HD. We hypothezised that htt interacting proteins might contribute to this variation in the AAO and investigated human htt-associated protein-1 (HAP1) using genetic and functional assays. We identified six polymorphisms in the HAP1 gene including one that substitutes methionine (M441) for threonine (T441) at amino acid 441. Analyzing 980 European HD patients, we found that patients homozygous for the M441 genotype show an 8-year delay in the AAO. Functional assays demonstrated that human M441-HAP1 interacts with mutant htt more tightly than does human T441-HAP1, reduces soluble htt degraded products and protects against htt-mediated toxicity. We thus provide genetic and functional evidence that the M441-HAP1 polymorphism modifies the AAO of HD.