Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features
Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features
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DOI：
10.1136/jmedgenet-2020-106861
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发表时间：
2021-03-01
影响因子：
4
通讯作者：
Zeviani, Massimo
中科院分区：
文献类型：
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作者：
Beninca, Cristiane;Zanette, Vanessa;Zeviani, Massimo
线粒体通过氧化磷酸化过程提供ATP，其物理位置位于线粒体内膜（IMM）。线粒体接触位点和组织系统（MICOS）复合体被称为“线粒体骨架”，因为它在维持IMM结构中起作用。APOO编码MIC26， MIC26是MICOS的一个组成部分，其在MICOS的维护或组装中的确切功能尚未完全阐明。方法我们研究了一个以进行性发育迟缓、乳酸酸中毒、肌无力、张力下降、体重减轻、胃肠和体温自主神经紊乱、重复感染、认知障碍和自闭症行为为主要症状的家庭。其他家族成员表现出不同的表型表现。全外显子组测序用于筛选病理变异。患者来源的皮肤成纤维细胞被用来证实APOO中发现的变异的致病性。利用果蝇和酿酒酵母的基因敲除模型验证MIC26参与MICOS组装和线粒体功能。结果在APOO中发现了可能致病的C . 350t >C转换，预测MIC26的I117T取代。该突变导致蛋白质在输入过程中加工受损，并错误地插入到IMM中。这与MICOS组装改变和嵴结破坏有关。在酵母和黑腹菌模型中，MIC26的相应突变或完全缺失与线粒体结构和功能缺陷有关。结论这是首例载脂蛋白o致病性突变，导致MICOS组装改变和神经肌肉损伤。MIC26参与MICOS在人、酵母和苍蝇体内的组装或稳定性。
BackgroundMitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture. APOO encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.MethodsWe have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in APOO. Knockout models in Drosophila melanogaster and Saccharomyces cerevisiae were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.ResultsA likely pathogenic c.350T>C transition was found in APOO predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and D. melanogaster models.ConclusionThis is the first case of pathogenic mutation in APOO, causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.