A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome.
A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome.
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DOI：
10.1093/hmg/ddx152
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发表时间：
2017-07-01
影响因子：
3.5
通讯作者：
Plomp AS
中科院分区：
文献类型：
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作者：
Chatzispyrou IA;Alders M;Guerrero-Castillo S;Zapata Perez R;Haagmans MA;Mouchiroud L;Koster J;Ofman R;Baas F;Waterham HR;Spelbrink JN;Auwerx J;Mannens MM;Houtkooper RH;Plomp AS
Perrault综合征（PS）是一种罕见的隐性遗传性疾病，以卵巢发育不全和感音神经性耳聋为特征。它在临床上和遗传上是异质性的，以前已经在不同的基因中描述了突变，主要与线粒体蛋白质稳态有关。我们诊断出三名不相关的女性患有PS，并着手使用外显子组测序来确定潜在的遗传原因。我们排除了已知PS基因的突变，但在ERAL 1基因中发现了一个纯合突变（c.707A > T; p.Asn236Ile）。由于ERAL 1蛋白与线粒体12 S rRNA结合，并参与线粒体核糖体小亚基的组装，因此鉴定的变体代表了可能的候选者。对ERAL 1的3D模型的计算机分析表明，突变的残基阻碍了蛋白质-底物相互作用，可能影响其功能。在分子基础上，PS皮肤成纤维细胞ERAL 1蛋白水平降低。细胞的复合体分析显示组装的小核糖体亚基水平总体降低，表明ERAL 1变体影响线粒体核糖体组装。此外，患者的12 S rRNA水平降低，并通过野生型ERAL 1的慢病毒表达进行拯救。在生理水平上，PS成纤维细胞的线粒体呼吸明显减少，证实线粒体功能紊乱。最后，C的击倒。线虫ERAL 1同源物E02 H1.2几乎完全阻断了蠕虫的产卵，模拟了受PS影响的妇女的生育能力受损。我们在患者细胞和蠕虫中的跨物种数据支持ERAL 1突变可以引起PS并与线粒体代谢变化相关的假设。
Perrault syndrome (PS) is a rare recessive disorder characterized by ovarian dysgenesis and sensorineural deafness. It is clinically and genetically heterogeneous, and previously mutations have been described in different genes, mostly related to mitochondrial proteostasis. We diagnosed three unrelated females with PS and set out to identify the underlying genetic cause using exome sequencing. We excluded mutations in the known PS genes, but identified a single homozygous mutation in the ERAL1 gene (c.707A > T; p.Asn236Ile). Since ERAL1 protein binds to the mitochondrial 12S rRNA and is involved in the assembly of the small mitochondrial ribosomal subunit, the identified variant represented a likely candidate. In silico analysis of a 3D model for ERAL1 suggested that the mutated residue hinders protein-substrate interactions, potentially affecting its function. On a molecular basis, PS skin fibroblasts had reduced ERAL1 protein levels. Complexome profiling of the cells showed an overall decrease in the levels of assembled small ribosomal subunit, indicating that the ERAL1 variant affects mitochondrial ribosome assembly. Moreover, levels of the 12S rRNA were reduced in the patients, and were rescued by lentiviral expression of wild type ERAL1. At the physiological level, mitochondrial respiration was markedly decreased in PS fibroblasts, confirming disturbed mitochondrial function. Finally, knockdown of the C. elegans ERAL1 homologue E02H1.2 almost completely blocked egg production in worms, mimicking the compromised fertility in PS-affected women. Our cross-species data in patient cells and worms support the hypothesis that mutations in ERAL1 can cause PS and are associated with changes in mitochondrial metabolism.
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DOI：
10.1042/bj20100757
发表时间：
2010-09-15
期刊：
The Biochemical journal
影响因子：
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作者：
Dennerlein S;Rozanska A;Wydro M;Chrzanowska-Lightowlers ZM;Lightowlers RN
通讯作者：
Lightowlers RN
影响因子：
4.4
作者：
Ahmed, Saleem;Jelani, Musharraf;Al-Aama, Jumana Yousuf
通讯作者：
Al-Aama, Jumana Yousuf
影响因子：
9.9
作者：
Crimi, M;Galbiati, S;Comi, GP
通讯作者：
Comi, GP
影响因子：
5.8
作者：
Giese, Heiko;Ackermann, Joerg;Koch, Ina
通讯作者：
Koch, Ina
影响因子：
12.3
作者：
通讯作者：
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