Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions
Identification and Characterization of New RNASEH1 Mutations Associated With PEO Syndrome and Multiple Mitochondrial DNA Deletions
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DOI：
10.3389/fgene.2019.00576
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发表时间：
2019-06-14
影响因子：
3.7
通讯作者：
Garcia-Arumi, Elena
中科院分区：
文献类型：
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作者：
Carreno-Gago, Lidia;Blazquez-Bermejo, Cora;Garcia-Arumi, Elena
线粒体DNA（mtDNA）缺失综合征包括一组由参与mtDNA复制和维持的基因突变引起的疾病。临床表型范围从致命的婴儿肝脑型到轻度成人发作的进行性眼外肌麻痹（PEO）。我们报告的情况下，与PEO和多个mtDNA缺失的患者，与两个新的纯合突变RNASEH 1。第一个突变（c.487>C）位于与先前报道的四个突变相同的催化结构域中，第二个突变（c.258_260del）位于连接结构域中，其中没有报道突变。对突变的计算机模拟研究预测只有第一个突变是致病的，但功能研究表明，这两个突变都会导致核糖核酸酶H1活性的丧失。在患者成纤维细胞中证实了mtDNA复制功能障碍，其在溴化乙锭诱导的mtDNA耗竭后不能恢复正常的mtDNA拷贝数。我们的研究结果证明了在PEO综合征、多重缺失和轻度线粒体肌病患者中发现的两种新的RNASEH 1变体的致病性。
Mitochondrial DNA (mtDNA) depletion and deletion syndrome encompasses a group of disorders caused by mutations in genes involved in mtDNA replication and maintenance. The clinical phenotype ranges from fatal infantile hepatocerebral forms to mild adult onset progressive external ophthalmoplegia (PEO). We report the case of a patient with PEO and multiple mtDNA deletions, with two new homozygous mutations in RNASEH1. The first mutation (c.487>C) is located in the same catalytic domain as the four previously reported mutations, and the second (c.258_260del) is located in the connection domain, where no mutations have been reported. In silico study of the mutations predicted only the first mutation as pathogenic, but functional studies showed that both mutations cause loss of ribonuclease H1 activity. mtDNA replication dysfunction was demonstrated in patient fibroblasts, which were unable to recover normal mtDNA copy number after ethidium bromide-induced mtDNA depletion. Our results demonstrate the pathogenicity of two new RNASEH1 variants found in a patient with PEO syndrome, multiple deletions, and mild mitochondrial myopathy.