Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Department Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
Clin Genet. 2023 Dec;104(6):659-668. doi: 10.1111/cge.14420. Epub 2023 Aug 30.
APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that causes a severe mitochondrial disease with overall progeria-like phenotypes in two patients. Both patients developed partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. The patients died at an early age of 12 or 18 months. Exome sequencing revealed a mutation (NM_024122.5): c.532G>T (p.E178*) in the APOO/MIC26 gene that causes a nonsense mutation leading to the loss of 20 C-terminal amino acids. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells. We conclude that the novel mutation found in the APOO/MIC26 gene is a loss-of-function mutation impairing mitochondrial morphology and cristae morphogenesis.
APOO/MIC26 是 MICOS 复合物的一个亚基，对于线粒体嵴的形态和功能是必需的。在这里，我们报道了一个 APOO/MIC26 基因的新型变异，该变异导致了两名患者出现严重的线粒体疾病，具有整体早衰样表型。两名患者均出现胼胝体部分发育不全、双侧先天性白内障、甲状腺功能减退和严重的免疫缺陷。患者分别在 12 个月和 18 个月时早夭。外显子组测序揭示了 APOO/MIC26 基因中的一个突变（NM_024122.5）：c.532G>T（p.E178*），导致无义突变，从而导致 20 个 C 末端氨基酸的缺失。该突变导致 MIC26 蛋白极不稳定且易于降解，但剩余的微量突变 MIC26 仍能正确定位于线粒体，并与其他 MICOS 亚基发生物理相互作用。表达携带相应 APOO/MIC26 突变的 MIC26 的 MIC26 KO 细胞显示，线粒体嵴结构紊乱，形态呈片段化，类似于 MIC26 KO 细胞。我们得出结论，在 APOO/MIC26 基因中发现的新型突变是一种功能丧失突变，会损害线粒体形态和嵴形态发生。
