2‐Oxoglutarate dehydrogenase (OGDH) is a rate‐limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α‐Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in both OGDH protein and enzyme activity. Transfection of human OGDH cDNA in HEK293 cells carrying p.N320S also produced significantly lower protein levels compared to those with wild‐type cDNA. Loss of Drosophila Ogdh (dOgdh) caused early developmental lethality, rescued by expressing wild‐type dOgdh (dOgdh^WT) or human OGDH (OGDH^WT) cDNA. In contrast, expression to the mutant OGDH (OGDH^N320S) or dOgdh carrying homologous mutations to human OGDH p.N320S variant (dOgdh^N324S) failed to rescue lethality of dOgdh null mutants. Knockdown of dOgdh in the nervous system resulted in locomotion defects which were rescued by dOgdh^WT expression but not by dOgdh^N324S expression. Collectively, the results indicate that c.959A>G variant in OGDH leads to an amino acid change (p.N320S) causing a severe loss of OGDH protein function. Our study establishes in the first time a genetic link between an OGDH gene mutation and OGDH deficiency.

中文翻译：

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OGDH 基因中的双等位基因致病性变异导致具有线粒体疾病特征的神经系统疾病


2-氧化戊二酸脱氢酶 (OGDH) 是线粒体 TCA 循环中的限速酶，由OGDH基因编码。此前曾报道α-酮戊二酸脱氢酶（OGDH）缺乏与发育迟缓、肌张力低下、运动障碍和代谢失代偿有关，但未提供遗传数据。通过全外显子组测序，我们鉴定出两个个体在OGDH基因中携带纯合错义变异 c.959A>G (p.N320S)。这些人表现出整体发育迟缓、乳酸升高、共济失调和癫痫发作。果蝇中的成纤维细胞分析和突变建模用于评估该变异的致病性。来自受试者 #2 的皮肤成纤维细胞显示 OGDH 蛋白和酶活性均下降。与野生型 cDNA 相比，在携带 p.N320S 的 HEK293 细胞中转染人 OGDH cDNA 也产生显着较低的蛋白质水平。果蝇 Ogdh ( dOgdh ) 的缺失导致早期发育死亡，可通过表达野生型dOgdh ( dOgdh ^WT ) 或人 OGDH ( OGDH ^WT ) cDNA 来挽救。相反，表达突变体 OGDH ( OGDH ^N320S ) 或携带与人OGDH p.N320S 变体 ( dOgdh ^N324S ) 同源突变的dOgdh未能挽救dOgdh无效突变体的致死率。神经系统中dOgdh的敲低会导致运动缺陷，这种缺陷可以通过dOgdh ^WT表达来挽救，但不能通过dOgdh ^N324S表达来挽救。 总的来说，结果表明OGDH中的 c.959A>G 变异会导致氨基酸变化 (p.N320S)，导致 OGDH 蛋白功能严重丧失。我们的研究首次确立了OGDH基因突变和 OGDH 缺乏之间的遗传联系。