GLUTARIC ACIDEMIA--MOLECULAR, BIOCHEMICAL, AND CHEMICAL HETEROGENEITY

1型谷氨酸血症（GA 1）是一种赖氨酸和色氨酸氧化的人类先天性缺陷，通常在并发感染期间或之后，由于基底神经节的急性变性，导致儿童进行性运动障碍。代谢性症状如酸中毒和低血糖症是罕见的，死亡通常发生在生命的第一个十年。这种情况是由于缺乏戊二酰辅酶A脱氢酶，一种含FAD的线粒体酶，可将戊二酰辅酶A氧化脱羧为CO2。我们对这种疾病的研究已经超过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，并鉴定了已知致病的许多突变中的大多数。该资助期的具体目标是继续对GA 1患者进行突变分析，并确定GCD突变在大肠杆菌中表达时的活性与两种不同突变的复合杂合子患者成纤维细胞中的GCD活性之间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，以确定网站的GCD活动在大脑中，我们将开发一个小鼠基因敲除模型的GA 1检查的影响，GCD缺乏对大脑发育和结构。与GA 1一样，D-2-羟基谷氨酸血症是一种遗传性神经系统疾病，几乎没有代谢后果。它是作为一种常染色体隐性遗传性状遗传的，在其严重的形式，这是一致的家庭，导致新生儿发作癫痫，张力减退，失明和发育迟缓。D-2-羟基谷氨酸蓄积的原因未知，其通常来源和处置也未知。已知D-2-羟基谷氨酸蓄积的原因是其通常来源和处置。积累的D-2-羟基谷氨酸或硫醇酯，生物化学和分子生物学的方法，提出检查的假设，这种疾病是由于遗传缺陷的这种脱氢酶。

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.