A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria
A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria
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DOI：
10.1073/pnas.0404840101
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发表时间：
2004-11-30
影响因子：
11.1
通讯作者：
Van Schaftingen, E
中科院分区：
文献类型：
--
作者：
Rzem, R;Veiga-da-Cunha, M;Van Schaftingen, E
本研究的目的是确定l -2-羟基戊二酸尿症的生化和遗传缺陷。l -2-羟基戊二酸尿症是一种神经代谢紊乱，其特征是尿、血浆和脑脊液中l -2-羟基戊二酸浓度升高。证据表明，在大鼠组织中存在一种fad依赖酶，专门催化l -2-羟基戊二酸氧化为α -酮戊二酸。这种酶主要在肝脏和肾脏中表达，但在心脏、大脑和其他组织中也有较低水平的表达。亚细胞分离表明肝酶存在于线粒体中，在那里它与膜结合。基于这些信息，数据库搜索导致鉴定出一个基因编码一个假设的蛋白质，与细菌fad依赖的苹果酸脱氢酶同源，并靶向线粒体。编码该蛋白的基因存在于染色体14q22.1上，在来自两个近亲家庭的l -2-羟基戊二酸尿患者中被发现在一个纯合区域。三个突变取代了高度保守的残基（Lys-71-Glu和Glu-176-Asp）或移除了外显子9，在来自三个不同家族的患者中被鉴定为纯合状态，并发现与疾病共分离。由此得出结论，l -2-羟基戊二酸在哺乳动物组织中正常代谢为a-酮戊二酸，l -2-羟基戊二酸尿是由l -2-羟基戊二酸脱氢酶基因突变引起的。因此，在这种代谢紊乱中观察到的病理结果必须是由于l -2-羟戊二酸对中枢神经系统的毒性作用。
The purpose of this study was to identify the biochemical and genetic defect in L-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by the presence of elevated concentrations Of L-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid. Evidence is provided for the existence in rat tissues of a FAD-dependent enzyme catalyzing specifically the oxidation of L-2-hydroxyglutarate to alpha-ketoglutarate. This enzyme is mainly expressed in liver and kidney but also at lower levels in heart, brain, and other tissues. Subcellular fractionation indicates that the liver enzyme is present in mitochondria, where it is bound to membranes. Based on this information, a database search led to the identification of a gene encoding a human hypothetical protein homologous to bacterial FAD-dependent malate dehydrogenases and targeted to mitochondria. The gene encoding this protein, present on chromosome 14q22.1, was found to be in a region homozygous in patients with L-2-hydroxyglutaric aciduria from two consanguineous families. Three mutations that replaced a highly conserved residue (Lys-71-Glu and Glu-176-Asp) or removed exon 9 were identified in homozygous state in patients from three distinct families and were found to cosegregate with the disease. it is concluded that L-2-hydroxyglutarate is normally metabolized to a-ketoglutarate in mammalian tissues and that L-2-hydroxyglutaric aciduria is caused by mutations in the gene that most likely encodes L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder must therefore be due to a toxic effect Of L-2-hydroxyglutarate on the central nervous system.