Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP
Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP
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U 盒蛋白 CHIP 泛素连接酶活性丧失导致共济失调和性腺功能减退。
DOI：
10.1093/hmg/ddt497
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发表时间：
2014-02-15
影响因子：
3.5
通讯作者：
Xu, Yu-Ming
中科院分区：
文献类型：
--
作者：
Shi, Chang-He;Schisler, Jonathan C.;Xu, Yu-Ming
戈登·霍姆斯综合征（GHS）是一种罕见的孟德尔神经退行性疾病，以共济失调和性腺功能减退为特征。最近，通过在E3连接酶RNF216和去泛素酶OTUD4的外显子组突变的发现，认为紊乱的泛素化是GHS的基础。我们对患有共济失调和性腺功能低下的三个兄弟姐妹中的两个进行了外显子组测序，并在STUB1 (NM_005861) c.737C→T, p.Thr246Met基因中发现了一个纯合突变，该基因编码蛋白质CHIP （hsc70相互作用蛋白的c端）。CHIP在调节蛋白质质量控制中发挥核心作用，部分是通过其作为E3连接酶的功能。在神经退行性疾病的几种遗传小鼠模型中，CHIP功能的丧失长期以来与蛋白质错误折叠和聚集有关；然而，CHIP在人类神经系统疾病中的作用尚未确定。在CHIP中引入Thr246Met突变导致泛素连接酶活性的丧失，直接使用重组蛋白和细胞培养模型测量。小鼠CHIP功能的丧失导致行为和生殖障碍，类似于人类共济失调和性腺功能减退。我们得出结论，GHS可能是由CHIP的功能缺失突变引起的。我们的研究结果进一步强调了无序泛素化和蛋白质质量控制在神经退行性疾病发病机制中的作用，并证明了将全外显子组测序与分子分析和动物模型相结合来确定因果疾病多态性的实用性。
Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.