Effects of a Mutation in the HSPE1 Gene Encoding the Mitochondrial Co-chaperonin HSP10 and Its Potential Association with a Neurological and Developmental Disorder.
Effects of a Mutation in the HSPE1 Gene Encoding the Mitochondrial Co-chaperonin HSP10 and Its Potential Association with a Neurological and Developmental Disorder.
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DOI：
10.3389/fmolb.2016.00065
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发表时间：
2016
影响因子：
5
通讯作者：
Bross P
中科院分区：
文献类型：
--
作者：
Bie AS;Fernandez-Guerra P;Birkler RI;Nisemblat S;Pelnena D;Lu X;Deignan JL;Lee H;Dorrani N;Corydon TJ;Palmfeldt J;Bivina L;Azem A;Herman K;Bross P
我们在这里报告的HSPE 1基因编码的HSP 10亚基的HSP 60/HSP 10伴侣蛋白复合物，协助蛋白质折叠在线粒体基质中的错义突变的分子调查。该突变是在一名婴儿中发现的，该婴儿在3个月大时因婴儿痉挛症而引起临床关注。临床外显子组测序揭示了HSPE 1 NM_002157.2：c.217C>T从头突变的杂合性，该突变导致HSP 10蛋白的第73位亮氨酸被苯丙氨酸取代。在公开的外显子组测序数据库或文献中从未观察到这种变异。为了评估突变是否可能与疾病相关，我们通过体外和离体研究研究了其影响。我们的体外研究表明，纯化的突变蛋白的功能，但其热稳定性，自发重折叠的倾向，并对蛋白水解处理的抗性被大大削弱。患者成纤维细胞的质谱分析显示几乎检测不到HSP 10-p.Leu73Phe蛋白的水平，导致HSP 10与HSP 60亚基的比率降低近2倍。线粒体超氧化物歧化酶SOD 2，一种蛋白质，其折叠是已知的强烈依赖于HSP 60/HSP 10复合物的量，减少到约20%，在患者成纤维细胞，尽管不变的SOD 2转录水平。作为一个可能的结果，线粒体超氧化物水平增加约2倍。虽然，我们不能排除其他的致病因素或贡献因素，我们的实验数据支持的概念，HSP 10-p.Leu73Phe突变可能是原因或一个强大的贡献因素，在所描述的患者的疾病。
We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature. To evaluate whether the mutation may be disease-associated we investigated its effects by in vitro and ex vivo studies. Our in vitro studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although, we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient.