Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency.
Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency.
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NFU1缺乏症患者的临床，生化和遗传谱。
DOI：
10.3389/fgene.2015.00123
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发表时间：
2015
影响因子：
3.7
通讯作者：
Haack TB
中科院分区：
文献类型：
--
作者：
Ahting U;Mayr JA;Vanlander AV;Hardy SA;Santra S;Makowski C;Alston CL;Zimmermann FA;Abela L;Plecko B;Rohrbach M;Spranger S;Seneca S;Rolinski B;Hagendorff A;Hempel M;Sperl W;Meitinger T;Smet J;Taylor RW;Van Coster R;Freisinger P;Prokisch H;Haack TB
线粒体能量代谢障碍在临床和遗传上是异质性的。一个越来越被认可的亚组是由缺陷的线粒体铁硫（Fe-S）簇生物合成引起的，迄今为止有13个基因的缺陷与人类疾病有关。其中三个突变，NFU 1，BOLA 3和IBA 57，影响线粒体[4Fe-4S]蛋白的组装，导致多种线粒体代谢途径和ATP产生的损害。这三种基因缺陷的患者表现为乳酸酸中毒、高甘氨酸血症和呼吸链复合物I和II、四种硫辛酸依赖性2-酮酸脱氢酶和甘氨酸裂解系统（GCS）的活性降低。迄今为止，在来自12个家族的15名患者中报告了5种不同的NFU 1致病性变体。我们报告了来自5个携带复合杂合或纯合致病性NFU 1突变的家族的7例新患者，通过候选基因筛选和外显子组测序鉴定。八个不同的疾病等位基因中有六个是新的，并进行了功能研究，以支持其中五个的致病性。特征性临床特征包括致死性婴儿脑病和肺动脉高压，导致7例患者中有6例在出生后6个月内死亡。实验室研究显示，骨骼肌和/或培养的皮肤成纤维细胞中丙酮酸脱氢酶复合物（五分之五）和呼吸链复合物I和II+III（五分之四）的组合缺陷以及乳酸盐（六分之五）和甘氨酸浓度增加（七分之七）。我们的研究有助于更好地定义与NFU 1突变相关的表型谱，并有助于未来患者的诊断。
Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron–sulfur (Fe–S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe–4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients.