Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy
Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy
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DOI：
10.1136/jmedgenet-2016-104212
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发表时间：
2017-05-01
影响因子：
4
通讯作者：
Rozet, Jean-Michel
中科院分区：
文献类型：
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作者：
Gerber, Sylvie;Ding, Martina G.;Rozet, Jean-Michel
研究背景非综合征型遗传性视神经病变（Non-syndromic hereditary optic neuropathy，HON）的发生与线粒体融合/分裂动力学基因、核和线粒体DNA编码的呼吸酶基因或线粒体功能未知的核基因突变有关。然而，致病基因在许多家庭中仍然未知。本研究的目的是确定非综合征型LHON样疾病的分子原因，在同胞出生的非血缘父母的法国血统。（基因定位和全外显子组测序）在一个非综合征性HON的多重家庭和患者的功能分析，结果发现NDUFS 2致病突变为复合杂合子（p.Tyr53Cys; p.Tyr308Cys）。使用患者来源的培养皮肤成纤维细胞的研究显示，NDUFS 2和复合物I丰度轻度降低，但呼吸链活性明显正常。在酵母Y. lipolytica直系同源NUCM，突变导致在没有复合物I和烟酰胺腺嘌呤二核苷酸泛醌氧化还原酶activity.Conclusions双等位基因NDUFS 2突变导致严重的复合物I缺乏症，先前已报道导致Leigh综合征与视神经病变。我们的研究结果与以下观点一致，即重度和亚型NDUFS 2突变的复合杂合性可导致非综合征型HON。这一观察结果表明NDUFS 2突变的严重程度与疾病的严重程度之间存在直接相关性，并进一步支持由于线粒体功能缺陷，非综合征型和综合征型HON之间存在遗传重叠。
Background Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin.Methods We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica.Results We identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively.Conclusions Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause nonsyndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.