BackgroundThe MRPS36 gene encodes a recently identified component of the 2‐oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the Krebs cycle catalyzing the oxidative decarboxylation of 2‐oxoglutarate to succinyl‐CoA. Defective OGDHC activity causes a clinically variable metabolic disorder characterized by global developmental delay, severe neurological impairment, liver failure, and early‐onset lactic acidosis.MethodsWe investigated the molecular cause underlying Leigh syndrome with bilateral striatal necrosis in two siblings through exome sequencing. Functional studies included measurement of the OGDHC enzymatic activity and MRPS36 mRNA levels in fibroblasts, assessment of protein stability in transfected cells, and structural analysis. A literature review was performed to define the etiological and phenotypic spectrum of OGDHC deficiency.ResultsIn the two affected brothers, exome sequencing identified a homozygous nonsense variant (c.283G>T, p.Glu95*) of MRPS36. The variant did not affect transcript processing and stability, nor protein levels, but resulted in a shorter protein lacking nine residues that contribute to the structural and functional organization of the OGDHC complex. OGDHC enzymatic activity was significantly reduced.The review of previously reported cases of OGDHC deficiency supports the association of this enzymatic defect with Leigh phenotypic spectrum and early‐onset movement disorder. Slightly elevated plasma levels of glutamate and glutamine were observed in our and literature patients with OGDHC defect.ConclusionsOur findings point to MRPS36 as a new disease gene implicated in Leigh syndrome. The slight elevation of plasma levels of glutamate and glutamine observed in patients with OGDHC deficiency represents a candidate metabolic signature of this neurometabolic disorder. © 2024 International Parkinson and Movement Disorder Society.

中文翻译：

---

MRPS36 的双等位基因变异体导致一种新形式的 Leigh 综合征

背景MRPS36该基因编码最近鉴定的 2-氧代戊二酸脱氢酶复合物 (OGDHC) 的一个成分，OGDHC 是克雷布斯循环的关键酶，催化 2-氧代戊二酸氧化脱羧为琥珀酰辅酶 A。 OGDHC 活性缺陷会导致临床上多变的代谢紊乱，其特征是整体发育迟缓、严重神经功能障碍、肝衰竭和早发性乳酸酸中毒。方法我们通过外显子组测序研究了两个兄弟姐妹伴有双侧纹状体坏死的 Leigh 综合征的分子病因。功能研究包括 OGDHC 酶活性的测量和MRPS36成纤维细胞中的 mRNA 水平、转染细胞中蛋白质稳定性的评估以及结构分析。我们进行了文献综述，以确定 OGDHC 缺乏症的病因和表型谱。结果在两个受影响的兄弟中，外显子组测序鉴定出纯合无义变异（c.283G>T，p.Glu95*）MRPS36。该变体不会影响转录物加工和稳定性，也不会影响蛋白质水平，但会导致蛋白质较短，缺少九个残基，而这些残基有助于 OGDHC 复合物的结构和功能组织。 OGDHC 酶活性显着降低。对先前报道的 OGDHC 缺乏病例的回顾支持这种酶缺陷与 Leigh 表型谱和早发性运动障碍的关联。在我们和文献报道的 OGDHC 缺陷患者中观察到血浆谷氨酸和谷氨酰胺水平略有升高。结论我们的研究结果表明MRPS36作为一种与 Leigh 综合征有关的新疾病基因。在 OGDHC 缺乏症患者中观察到的血浆谷氨酸和谷氨酰胺水平略有升高，代表了这种神经代谢紊乱的候选代谢特征。 © 2024 国际帕金森和运动障碍协会。