We report a patient carrying a novel pathogenic variant p.(Tyr101Cys) in ISCA1 leading to MMDS type 5. He initially presented a psychomotor regression with loss of gait and language skills and a tetrapyramidal spastic syndrome. Biochemical analysis of patient fibroblasts revealed impaired lipoic acid synthesis and decreased activities of complex I and II of respiratory chain. While ISCA1 is involved in mitochondrial machinery of iron-sulfur cluster biogenesis, these dysfunctions are secondary to impaired maturation of mitochondrial proteins containing the [4Fe-4S] clusters. Expression and purification of the human ISCA1 showed a decreased stability of the [2Fe-2S] cluster in the mutated protein.

中文翻译：

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扩大线粒体疾病的表型：ISCA1 中的新致病变异导致蛋白质中铁硫簇的不稳定性

我们报告了一名携带 ISC​​A1 新致病性变异 p.(Tyr101Cys) 导致 MMDS 5 型的患者。他最初表现为精神运动退化，步态和语言技能丧失以及四锥体痉挛综合征。患者成纤维细胞的生化分析显示硫辛酸合成受损，呼吸链复合物 I 和 II 活性降低。虽然 ISCA1 参与铁硫簇生物发生的线粒体机制，但这些功能障碍继发于含有 [4Fe-4S] 簇的线粒体蛋白的成熟受损。人 ISCA1 的表达和纯化表明突变蛋白中 [2Fe-2S] 簇的稳定性降低。