与线粒体疾病相关的临床病理和分子谱系
Clinicopathologic and molecular spectrum of -related mitochondrial disease.
作者信息
Bugiardini Enrico, Poole Olivia V, Manole Andreea, Pittman Alan M, Horga Alejandro, Hargreaves Iain, Woodward Cathy E, Sweeney Mary G, Holton Janice L, Taanman Jan-Willem, Plant Gordon T, Poulton Joanna, Zeviani Massimo, Ghezzi Daniele, Taylor John, Smith Conrad, Fratter Carl, Kanikannan Meena A, Paramasivam Arumugam, Thangaraj Kumarasamy, Spinazzola Antonella, Holt Ian J, Houlden Henry, Hanna Michael G, Pitceathly Robert D S
机构信息
MRC Centre for Neuromuscular Diseases (E.B., O.V.P., A.M., A.H., J.L.H., H.H., M.G.H., R.D.S.P.), UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (A.M., A.M.P., J.L.H., H.H., M.G.H.), Division of Neuropathology (J.L.H.), Department of Clinical Neuroscience (J.-W.T., A.S., I.J.H.), UCL Institute of Neurology; Neurometabolic Unit (I.H.), Neurogenetics Unit (C.E.W., M.G.S.), Department of Neuro-ophthalmology (G.T.P.), National Hospital for Neurology and Neurosurgery, London; Nuffield Department of Obstetrics and Gynaecology (J.P.), University of Oxford; MRC-Mitochondrial Biology Unit (M.Z.), Cambridge, UK; Unit of Molecular Neurogenetics (D.G.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Oxford Medical Genetics Laboratories (J.T., C.S., C.F.), Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, UK; Department of Neurology (M.A.K.), Nizam's Institute of Medical Sciences; CSIR-Centre for Cellular and Molecular Biology (A.P., K.T.), Hyderabad, Telangana, India; MRC Mill Hill Laboratory (I.J.H.), London, UK; Biodonostia Research Institute (I.J.H.), San Sebastián, Spain; and Department of Basic and Clinical Neuroscience (R.D.S.P.), Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.
出版信息
Neurol Genet. 2017 May 2;3(3):e149. doi: 10.1212/NXG.0000000000000149. eCollection 2017 Jun.
OBJECTIVE
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 () mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations.
METHODS
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 mutations was subsequently undertaken.
RESULTS
Pathogenic c.424G>A p.Val142Ile mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further mutations were confirmed. -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 -related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families.
CONCLUSIONS
In our cohort, mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in , , and . genetic analysis should also be considered in all patients with -negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.
目的
病理性核糖核酸酶H1（RNase H1）可导致异常的线粒体DNA（mtDNA）分离，并与多种mtDNA缺失相关。我们旨在确定线粒体疾病患者中RNase H1基因（）突变的发生率，并建立具有临床意义的基因型-表型相关性。
方法
对以下患者的进行了分析：（1）肌肉mtDNA存在多种缺失/耗竭的患者；（2）具有线粒体功能障碍神经病理学证据的孟德尔遗传性进行性眼外肌麻痹（PEO）患者，但未检测到肌肉mtDNA的多种缺失/耗竭。随后对新发现的和先前报道的携带突变的患者进行了临床病理和分子评估。
结果
在74名先证者中，有3个家系检测到致病性c.424G>A p.Val142Ile突变。鉴于所有3个家族都有印度血统，对另外50名具有与多种mtDNA缺失相关的不同临床表现的印度先证者进行了基因分析，但未确认进一步的突变。与相关的线粒体疾病的特征为PEO（100%）、小脑共济失调（57%）和吞咽困难（50%）。1例患者出现共济失调神经病谱系表型。尽管c.424G>A p.Val142Ile突变是所有报道的与相关的线粒体疾病的基础，但单倍型分析表明，我们家族中的该变体起源独立，而非源于奠基者事件。
结论
在我们的队列中，突变是成人孟德尔遗传性PEO伴多种mtDNA缺失的第四大常见病因，仅次于、和的突变。对于所有共济失调神经病谱系检测结果为阴性的患者，也应考虑进行基因分析。c.424G>A p.Val142Ile突变损害人类RNase H1的病理生理机制值得进一步研究。
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