与神经病变和视神经萎缩有关的同卵NDUFS6变体

IF 3.2 4区 医学 Q2 CLINICAL NEUROLOGY
A. Gangfuss, Philipp Rating, Tomas Ferreira, A. Hentschel, A. D. Marina, Heike Kölbel, A. Sickmann, A. Abicht, Florian Kraft, Tobias Ruck, Johann Böhm, Anne Schänzer, Ulrike Schara-Schmidt, Teresa M. Neuhann, Rita Horvath, Andreas Roos
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引用次数: 0

摘要

背景:NADH 脱氢酶[泛醌]铁硫蛋白 6(NDUFS6)基因编码线粒体膜呼吸链 NADH 脱氢酶(复合物 I)的辅助亚基。NDUFS6 双等位基因变异与一种严重的疾病有关,这种疾病大多被报道为致死性婴幼儿线粒体病(LMID)或利氏综合征(LS)。目的:在这里,我们在一名男性患者身上发现了 NDUFS6 的一个同源变异体(c.309 + 5 G > A),该患者患有轴突性神经病,皮肤活检结果显示伴有小纤维缺失,并进一步并发视神经萎缩和边缘性智力障碍。研究方法为研究该变异的致病性,对患者来源的白细胞进行了生化研究(mtDNA拷贝数定量、ELISA、蛋白质组分析)。结果显示分析发现,NDUFS6 蛋白的缺失与另外三种线粒体 NADH 脱氢酶亚基/组装蛋白(NDUFA12、NDUFS4 和 NDUFV1)的减少有关。白细胞中的线粒体拷贝数没有改变,血清中的线粒体生物标志物 GDF15 也没有显著变化。结论因此,我们的临床和生化综合数据加强了 NDUFS6 是一种非常罕见的伴有视神经萎缩和边缘性智力障碍的轴索神经病的致病因子的概念,从而扩大了(i)神经病的分子遗传学范围和(ii)NDUFS6 相关表型的临床范围。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy
Background: The NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 (NDUFS6) gene encodes for an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Bi-allelic NDUFS6 variants have been linked with a severe disorder mostly reported as a lethal infantile mitochondrial disease (LMID) or Leigh syndrome (LS). Objective: Here, we identified a homozygous variant (c.309 + 5 G >  A) in NDUFS6 in one male patient with axonal neuropathy accompanied by loss of small fibers in skin biopsy and further complicated by optic atrophy and borderline intellectual disability. Methods: To address the pathogenicity of the variant, biochemical studies (mtDNA copy number quantification, ELISA, Proteomic profiling) of patient-derived leukocytes were performed. Results: The analyses revealed loss of NDUFS6 protein associated with a decrease of three further mitochondrial NADH dehydrogenase subunit/assembly proteins (NDUFA12, NDUFS4 and NDUFV1). Mitochondrial copy number is not altered in leukocytes and the mitochondrial biomarker GDF15 is not significantly changed in serum. Conclusions: Hence, our combined clinical and biochemical data strengthen the concept of NDUFS6 being causative for a very rare form of axonal neuropathy associated with optic atrophy and borderline intellectual disability, and thus expand (i) the molecular genetic landscape of neuropathies and (ii) the clinical spectrum of NDUFS6-associated phenotypes.
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来源期刊
Journal of neuromuscular diseases
Journal of neuromuscular diseases Medicine-Neurology (clinical)
CiteScore
5.10
自引率
6.10%
发文量
102
期刊介绍: The Journal of Neuromuscular Diseases aims to facilitate progress in understanding the molecular genetics/correlates, pathogenesis, pharmacology, diagnosis and treatment of acquired and genetic neuromuscular diseases (including muscular dystrophy, myasthenia gravis, spinal muscular atrophy, neuropathies, myopathies, myotonias and myositis). The journal publishes research reports, reviews, short communications, letters-to-the-editor, and will consider research that has negative findings. The journal is dedicated to providing an open forum for original research in basic science, translational and clinical research that will improve our fundamental understanding and lead to effective treatments of neuromuscular diseases.
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