Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency.
Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency.
复制标题
DOI：
10.1016/j.bbacli.2014.12.003
复制
发表时间：
2015-06-01
期刊：
影响因子：
--
通讯作者：
Giulivi C
中科院分区：
文献类型：
--
作者：
Fujisawa Y;Napoli E;Wong S;Song G;Yamaguchi R;Matsui T;Nagasaki K;Ogata T;Giulivi C
家族性糖皮质激素缺乏症（FGD）是一种罕见的常染色体隐性遗传疾病，其特征是孤立的糖皮质激素缺乏症。最近，编码线粒体烟酰胺核苷酸转氢酶（NNT）的基因突变已被确定为 FGD 的致病基因；然而，在携带 NNT 突变的 FGD 患者中尚未报告有 NNT 活性。对来自 FDG 纯合子和杂合子携带者的淋巴细胞进行 F215S NNT 突变的临床、生化和分子分析。在这项研究中，我们描述了一名受 FGD 影响的日本患者，该患者携带一种新型 NNT 纯合突变（c.644T>C；F215S），其外周血细胞线粒体功能显着丧失（NNT 活性=健康对照的 31%）。突变杂合父母的 NNT 活性是对照的 61%。我们的结果表明 (i) 线粒体生物发生（柠檬酸合酶活性）和/或 mtDNA 复制（mtDNA 拷贝数）在 NNT 活性≤60% 时受到影响，因为这些参数在携带一个或两个突变等位基因的个体中受到影响； (ii) 其他结果（mtDNA 缺失、蛋白质酪氨酸硝化、OXPHOS 能力）在 ≤ 30% NNT 活性时受到影响，这也在 C57BL/6J (NNT−/−) 与 C57BL/6JN (NNT+/+) 亚系的小鼠小脑线粒体中观察到。通过研究受 NNT 基因新点突变影响的家庭，发现了各种线粒体结果的基因剂量反应，为 NNT 在维持线粒体 DNA 完整性方面的作用提供了新的见解，超出了预防氧化应激的描述。据报道，一部分 FGD 患者存在 NNT 突变。据报道，一种新型 NNT 致病性突变 (c.644T > C) 存在基因剂量效应。纯合子携带者（FGD 患者）的 NNT 活性可以忽略不计。患者表现出 OXPHOS 缺陷，线粒体 DNA 和蛋白质发生氧化损伤。杂合子携带者（父母）无症状，NNT 活性约为 60%。所有携带者均表现出线粒体生物合成和线粒体DNA复制缺陷。
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency. Recently, mutations in the gene encoding for the mitochondrial nicotinamide nucleotide transhydrogenase (NNT) have been identified as a causative gene for FGD; however, no NNT activities have been reported in FGD patients carrying NNT mutations. Clinical, biochemical and molecular analyses of lymphocytes from FDG homozygous and heterozygous carriers for the F215S NNT mutation were performed. In this study, we described an FGD-affected Japanese patient carrying a novel NNT homozygous mutation (c.644T>C; F215S) with a significant loss-of-function (NNT activity = 31% of healthy controls) in peripheral blood cells' mitochondria. The NNT activities of the parents, heterozygous for the mutation, were 61% of the controls. Our results indicated that (i) mitochondrial biogenesis (citrate synthase activity) and/or mtDNA replication (mtDNA copy number) were affected at ≤ 60% NNT activity because these parameters were affected in individuals carrying either one or both mutated alleles; and (ii) other outcomes (mtDNA deletions, protein tyrosine nitration, OXPHOS capacity) were affected at ≤ 30% NNT activity as also observed in murine cerebellar mitochondria from C57BL/6J (NNT−/−) vs. C57BL/6JN (NNT+/+) substrains. By studying a family affected with a novel point mutation in the NNT gene, a gene–dose response was found for various mitochondrial outcomes providing for novel insights into the role of NNT in the maintenance of mtDNA integrity beyond that described for preventing oxidative stress. Mutations in NNT were reported for a subset of FGD patients. A gene–dose effect is reported for a novel NNT pathogenic mutation (c.644T > C). Homozygous carrier (FGD patient) has negligible NNT activity. Patient exhibited OXPHOS deficits with oxidative damage to mtDNA and proteins. Heterozygous carriers (parents) were asymptomatic with ~ 60% NNT activity. All carriers showed deficits in mitochondrial biogenesis and mtDNA replication.