Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease.
Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease.
复制标题
DOI：
10.1212/nxg.0000000000000149
复制
发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Pitceathly RDS
中科院分区：
文献类型：
--
作者：
Bugiardini E;Poole OV;Manole A;Pittman AM;Horga A;Hargreaves I;Woodward CE;Sweeney MG;Holton JL;Taanman JW;Plant GT;Poulton J;Zeviani M;Ghezzi D;Taylor J;Smith C;Fratter C;Kanikannan MA;Paramasivam A;Thangaraj K;Spinazzola A;Holt IJ;Houlden H;Hanna MG;Pitceathly RDS
病理性核糖核酸酶H1(RNaseH1)导致线粒体DNA(MtDNA)的异常分离，并与mtDNA的多个缺失有关。我们的目的是确定线粒体疾病患者中RNaseH1基因(RNASEH1)突变的发生率，并建立有临床意义的基因-表型相关性。对有(1)肌肉mtDNA多发性缺失/缺失和(2)孟德尔进行性眼外肌麻痹(PEO)伴线粒体功能障碍的神经病理学证据，但未检测到肌肉mtDNA多发性缺失/缺失的患者进行了RNASEH1分析。随后对新发现的和以前报告的携带RNASEH1突变的患者进行了临床病理和分子评估。在74个先证者中，有3个家系检测到致病基因c.424G>；A p.Val142Ile RNase-H1突变。考虑到所有3个家族都有印度血统，对另外50名印度先证者进行了RNASEH1基因分析，这些先证者的临床表现与多个mtDNA缺失有关，但没有进一步证实RNASEH1突变。与RNASEH1相关的线粒体疾病以PEO(100%)、小脑性共济失调(57%)和吞咽困难(50%)为特征。1例患者出现共济失调神经病谱表型。虽然C.424G>；A p.Val142Ile突变是所有已报道的RNASEH1相关线粒体疾病的基础，但单倍型分析表明，我们家族中的该变异有独立的起源，而不是创始人事件。在我们的队列中，RNASEH1突变是成人孟德尔人PEO与多个mtDNA缺失相关的第四大常见原因，仅次于Polg、RRM2B和TWNK突变。对于所有Polg阴性共济失调神经病谱的患者，也应考虑进行RNASEH1基因分析。C.424G>；A p.Val142Ile突变损伤人RNaseH1的病理生理机制值得进一步研究。
Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations. RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring RNASEH1 mutations was subsequently undertaken. Pathogenic c.424G>A p.Val142Ile RNASEH1 mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, RNASEH1 genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further RNASEH1 mutations were confirmed. RNASEH1-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported RNASEH1-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families. In our cohort, RNASEH1 mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in POLG, RRM2B, and TWNK. RNASEH1 genetic analysis should also be considered in all patients with POLG-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.