Perrault Syndrome Is Caused by Recessive Mutations in CLPP, Encoding a Mitochondrial ATP-Dependent Chambered Protease
Perrault Syndrome Is Caused by Recessive Mutations in CLPP, Encoding a Mitochondrial ATP-Dependent Chambered Protease
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DOI：
10.1016/j.ajhg.2013.02.013
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发表时间：
2013-04-04
影响因子：
9.8
通讯作者：
Newman, William G.
中科院分区：
文献类型：
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作者：
Jenkinson, Emma M.;Rehman, Atteeq U.;Newman, William G.
Perrault综合征是一种遗传和临床异质性常染色体隐性疾病，其特征是感音神经性听力损失和卵巢功能衰竭。通过对三个家系的连锁分析、纯合性作图和外显子组测序，我们确定CLPP突变可能是导致这种表型的原因。在每个家族中，受影响的个体是不同致病性CLPP等位基因的纯合子：c.433A>C（p.Thr145Pro），c.440G>C（p.Cys147Ser），或实验证明的剪接供体位点突变，c.270+4A>G。CLPP是线粒体ATP依赖性蛋白水解复合物的组分，是由CLPP编码的高度保守的内肽酶，并且形成进化上古老的线粒体未折叠蛋白反应（UPRmt）应激信号传导途径的元件。晶体结构建模表明，这两种取代将改变CLPP桶室的结构，捕获未折叠的蛋白质，并将它们暴露于蛋白水解。与先前鉴定的编码线粒体组氨酰-tRNA合成酶的HARS 2突变一起，CLPP突变揭示了线粒体蛋白质稳态功能障碍是Perrault综合征的原因。
Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270+4A>G. CLPP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by CLPP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPRmt) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the CLPP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in CLPP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome.