Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15706 Santiago de Compostela, Spain.
Rare Diseases Networking Biomedical Research Centre (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15706 Santiago de Compostela, Spain.
Int J Mol Sci. 2021 Dec 15;22(24):13484. doi: 10.3390/ijms222413484.
Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. , a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient's DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient's fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient's fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant.
线粒体功能的完整性取决于线粒体膜中蛋白质和脂质的动态平衡，而它们的积累失调可能导致疾病。酰基辅酶 A 甘油激酶（ACGPK）不仅参与脂质信号转导，还是线粒体内膜 TIM22 复合物的组成部分，该复合物介导一组膜蛋白的输入。ACGPK 基因突变既可以改变磷脂代谢，又可以改变线粒体蛋白的生物发生，导致 Sengers 综合征的发病机制。我们描述了一名携带新型纯合 c.518+1G>A 变异的婴儿病例，该婴儿出生时患有先天性白内障、皮氏扩张、严重先天性扩张性心肌病和高乳酸血症，并在出生后 20 小时死亡。使用患者的 DNA，我们对编码呼吸链复合物亚基和参与线粒体氧化磷酸化（OXPHOS）的线粒体蛋白的 314 个核基因进行了靶向测序。检测到 cDNA 序列长度减少了 96-bp。患者成纤维细胞的耗氧量（OCR）和 OCR:ECAR（细胞外酸化率）比值降低表明电子流通过呼吸链减少，分光光度法显示 OXPHOS 复合物 I 和 V 的活性降低。我们证明了患者成纤维细胞中线粒体功能明显缺陷，并描述了这种新型 ACGPK 变异导致发病的可能分子机制。使用体外分析进行的实验验证允许对致病变异进行准确的特征描述。
