GLUTARIC ACIDEMIA--MOLECULAR, BIOCHEMICAL, AND CHEMICAL HETEROGENEITY

1型戊二酸血症（GA1）是一种人类先天性赖氨酸和色氨酸氧化错误，通常在并发感染期间或之后，由于基底节区急性变性导致儿童进行性运动障碍。代谢症状如酸中毒和低血糖是罕见的，死亡通常发生在生命的头十年。这种情况是由于缺乏戊二酰辅酶a脱氢酶，这是一种含有fad的线粒体酶，可将戊二酰辅酶a氧化脱羧为二氧化碳。我们研究这种疾病已经超过25年，是第一个描述这种疾病并描述其有机酸尿，神经病理学和酶缺陷的人。我们还克隆并表达了编码GCD的人类cDNA，并确定了大多数已知的致病突变。该资助期的具体目标是继续对GA1患者进行突变分析，并确定在大肠杆菌中表达的GCD突变活性与两种不同突变的复合杂合子患者的成纤维细胞中GCD活性偶尔存在差异的原因。这将通过在大肠杆菌中共表达不同的GCD突变来完成，并确定某些突变蛋白之间是否发生基因内互补。此外，现在已经使用基因敲除技术来确定大脑中GCD活性的位点，我们将开发GA1的小鼠敲除模型，以检查GCD缺乏对大脑发育和结构的影响。与GA1一样，d -2-羟基戊二酸血症是一种遗传性神经系统疾病，几乎没有代谢后果。它是一种常染色体隐性遗传性状，其严重形式在家族中是一致的，可导致新生儿癫痫发作、张力低下、失明和发育迟缓。d -2-羟基戊二酸积累的原因尚不清楚，其通常的来源和处置也不清楚。d -2-羟基戊二酸积累的原因是已知的，作为其通常的来源和处置。d -2-羟基戊二酸或硫醇酯的积累，以及生物化学和分子生物学的方法被提出来检验这种疾病是由于遗传缺乏这种脱氢酶的假设。

Glutaric acidemia type 1 (GA1) is a human inborn error of lysine and tryptophan oxidation which causes a progressive movement disorder in childhood due to acute degeneration of the basal ganglia, usually during or following an intercurrent infection. Metabolic signs such as acidosis and hypoglycemia are rare, and death usually occurs during the first decade of life. The condition is due to deficiency of glutaryl-CoA dehydrogenase, an FAD-containing mitochondrial enzyme which oxidatively decarboxylates glutaryl-CoA to CO2. We have been studying this disorder for more than twenty-five years, being the first to describe the disease and to characterize its organic aciduria, neuropathology, and enzyme defect. We also cloned and expressed human cDNA encoding GCD, and have identified most of the many mutations that are known to be disease-causing. Specific aims for this funding period are to continue mutation analysis in GA1 patients, and to determine the reasons for the occasional discrepancy between the activity of GCD mutations when expressed in E coli and GCD activity in fibroblasts of patients who are compound heterozygotes for two different mutations. This will be done by co-expressing the different GCD mutations in E coli, and determine if intragenic complementation occurs between certain mutant proteins. Also, having now used gene knockout technology to identify sites of GCD activity in the brain, we will develop a murine knockout model of GA1 to examine the effect of GCD deficiency on brain development and structure. Like GA1, D-2-hydroxyglutaric acidemia is an inherited neurologic disease with few metabolic consequences. It is inherited as an autosomal recessive trait and in its severe form, which is consistent within families, causes neonatal onset of seizures, hypotonia, blindness and developmental delay. The cause of D-2-hydroxyglutaric acid accumulation is unknown, as is its usual source and disposition. The cause of D-2-hydroxyglutaric acid accumulation is known, as its usual source and disposition. The accumulation of D-2-hydroxyglutaric acid or a thiol ester, and biochemical and molecular biology approaches are proposed to examine the hypothesis that the disorder is due to inherited deficiency of this dehydrogenase.