Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder.
Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder.
复制标题
DOI：
10.1016/j.ajhg.2018.01.020
复制
发表时间：
2018-03-01
影响因子：
9.8
通讯作者：
Wheeler MT
中科院分区：
文献类型：
--
作者：
Oláhová M;Yoon WH;Thompson K;Jangam S;Fernandez L;Davidson JM;Kyle JE;Grove ME;Fisk DG;Kohler JN;Holmes M;Dries AM;Huang Y;Zhao C;Contrepois K;Zappala Z;Frésard L;Waggott D;Zink EM;Kim YM;Heyman HM;Stratton KG;Webb-Robertson BM;Undiagnosed Diseases Network;Snyder M;Merker JD;Montgomery SB;Fisher PG;Feichtinger RG;Mayr JA;Hall J;Barbosa IA;Simpson MA;Deshpande C;Waters KM;Koeller DM;Metz TO;Morris AA;Schelley S;Cowan T;Friederich MW;McFarland R;Van Hove JLK;Enns GM;Yamamoto S;Ashley EA;Wangler MF;Taylor RW;Bellen HJ;Bernstein JA;Wheeler MT
ATP合成酶，H+转运，线粒体F1复合物，δ亚基（ATP 5 F1 D;以前称为ATP 5D）是线粒体ATP合成酶的一个亚基，在质子转运和ATP产生的偶联中起重要作用。在这里，我们描述了两个人，每个人都具有ATP 5 F1 D的纯合错义变体，他们表现出阵发性嗜睡、代谢性酸中毒、3-甲基戊烯二酸尿症和高氨血症。受试者1，c.245C>T（p.Pro82Leu）纯合子，在新生儿期开始出现复发性代谢失代偿，受试者2，c.317T>G（p.Val106Gly）纯合子，在儿童期出现急性脑病。培养的皮肤成纤维细胞从这些人表现出受损的装配F1 FO ATP合酶和随后降低复合物V活性。来自受试者1的细胞也表现出线粒体嵴的显着减少。果蝇ATPsynδ（ATP 5 F1 D同源物）在发育中的眼睛和大脑中的敲低导致苍蝇头部几乎完全丧失，这是一种被野生型人类ATP 5 F1 D完全拯救的表型。相比之下，ATP 5 F1 D c.245C>T和c.317T>G变体的表达挽救了头部大小表型，但重现了在线粒体氧化磷酸化缺陷的其他遗传模型中观察到的眼睛和触角缺陷。我们的数据确定ATP 5 F1 D中的c.245C>T（p.Pro82Leu）和c.317T>G（p.Val106Gly）是导致孟德尔线粒体疾病的致病性变体，其特征在于间歇性代谢失代偿。
ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.