BACKGROUND Combined oxidative phosphorylation deficiency 35 (COXPD 35) is a very rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the TRIT1 gene on chromosome 1p34. Only six cases of COXPD 35 and six allelic variants of TRIT1 gene mutations have been reported worldwide. CASE DESCRIPTION We describe two siblings who presented with similar clinical features including severe intellectual disability and epilepsy with onset of symptom in early infancy. RESULTS The whole exome sequencing results revealed a compound heterozygous novel variant, c.979G > A (p.Glu327Lys) and c.682 + 2 T > C, on TRIT1 exon 8 and intron 5, respectively, which was confirmed by Sanger sequencing. Protein structure analysis revealed that the p.Glu327Lys variant disrupts the conformation and electrostatic charge of the zinc-finger motif in the tRNA isopentenyltransferase (IPT), impairing binding of the mutant IPT to specific DNA sequences. CONCLUSION This is the first report of two Korean siblings with COXPD 35 with two novel variants in TRIT1. This study will help to understand the various phenotypic spectra in patients with COXPD 35 and to expand knowledge on the mechanisms of the disease based on genetic features.

中文翻译：

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韩国首例合并氧化磷酸化缺陷的病例 35 经临床和分子研究证实，两个兄弟姐妹中有两个新的 TRIT1 突变

背景联合氧化磷酸化缺陷 35 (COXPD 35) 是一种非常罕见的常染色体隐性遗传病，由染色体 1p34 上 TRIT1 基因的纯合或复合杂合突变引起。全世界仅报告了 6 例 COXPD 35 和 6 例 TRIT1 基因突变的等位基因变异。病例描述 我们描述了两个具有相似临床特征的兄弟姐妹，包括在婴儿早期出现症状的严重智力障碍和癫痫。结果 全外显子测序结果显示，TRIT1 外显子8 和内含子5 上分别存在复合杂合新变异，c.979G > A (p.Glu327Lys) 和c.682 + 2 T > C，Sanger 测序证实了这一点。蛋白质结构分析表明，p。Glu327Lys 变体破坏了 tRNA 异戊烯基转移酶 (IPT) 中锌指基序的构象和静电荷，从而削弱了突变 IPT 与特定 DNA 序列的结合。结论 这是关于 COXPD 35 的两个韩国兄弟姐妹在 TRIT1 中有两个新变体的第一份报告。这项研究将有助于了解 COXPD 35 患者的各种表型谱，并扩展基于遗传特征的疾病机制的知识。