Mitochondrial calcium homeostasis is a tightly controlled process that is required for a variety of cellular functions. The mitochondrial calcium uniporter complex plays a critical role in this process. MICU2 is a major component of the mitochondrial calcium uniporter complex and its deficiency has been shown to impair mitochondrial calcium [Ca²⁺]_m homeostasis although the exact mechanism remains unclear. We used exome sequencing, positional mapping, and functional characterization of MICU2 deficiency to investigate the role of MICU2 in calcium homeostasis. Using combined autozygome/exome analysis, a homozygous truncating mutation in MICU2 was found to fully segregate with a neurodevelopmental disorder in the form of severe cognitive impairment, spasticity, and white matter involvement in a multiplex consanguineous family. Patient-derived MICU2-deficient cells displayed impaired [Ca²⁺]_m homeostasis, with associated increase in mitochondrial sensitivity to oxidative stress, and abnormal regulation of inner mitochondrial membrane potential. This is the first demonstration of MICU2 deficiency in humans, which we suggest causes a distinct neurodevelopmental phenotype secondary to impaired mitochondrial calcium uniporter-mediated regulation of intracellular calcium homeostasis.

中文翻译：

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MICU2的无效突变会导致线粒体钙稳态异常和严重的神经发育障碍

线粒体钙动态平衡是各种细胞功能所需的严格控制的过程。线粒体钙单向复合物在此过程中起关键作用。MICU2是线粒体钙单向转运体复合物的主要组分，其不足已经显示损害线粒体化钙[Ca ²⁺ ]_米虽然确切的机制仍不清楚动态平衡。我们使用了外显子组测序，位置定位和MICU2缺乏症的功能特征来研究MICU2在钙稳态中的作用。使用组合autozygome /外显子组分析，以纯合子突变截断MICU2被发现以多重认知近亲家族的严重认知障碍，痉挛和白质受累的形式与神经发育障碍完全隔离。患者来源的MICU2缺陷细胞表现受损的[Ca ²⁺ ]_米稳态，在线粒体灵敏度氧化应激相关的增加，并且内线粒体膜电位的异常调节。这是人类中MICU2缺乏的首次证明，我们认为这是继线粒体钙单向蛋白介导的细胞内钙稳态调节受损后继发的独特神经发育表型。