COMMON POLYMORPHISM EFFECTS ON UREA CYCLE FUNCTION

氨代谢缺陷的分子研究已被普遍认为 仅限于罕见的先天新陈代谢障碍。然而，高氨血症， 更常见，并与非遗传性疾病有关 暴露在环境中。这些条件通常在一定程度上 身体上的肝脏损伤或破坏。一个常见的例子是 服药后患者出现频繁的高氨血症 丙戊酸这种药物。随着骨髓移植的增加 据报道，在BMT(BMT)过程中，出现了一些高氨血症死亡病例。 此外，更多微妙的毒性可能是由于 尿素循环前体(谷氨酰胺、丙氨酸、甘氨酸等)，或减少 在尿素循环中间体(精氨酸和瓜氨酸)中。不管是什么 触发事件，氨清除中的干扰反映了物理或 生物化学对尿素循环的影响。我的研究主要集中在 对编码第一个限速步骤的基因进行表征 尿失禁，氨基甲酰磷酸合成酶I(CPSI)。住院病人 研究中，我发现了一些罕见的CPSI分子缺陷 在严重的遗传性尿素循环中断中。在这些研究中， 我还发现了一种常见的外显子多态，它可能 定性地影响CPSI功能。这项研究旨在检查 该基因多态在临床和生化方面的意义 确定CPSI基因中其他潜在的相关变化。这些 变化可能在尿素循环毒性易感性中起关键作用 继发于药物或毒素暴露。我会研究一下功能 利用定点技术研究这种变化对CPSI蛋白表达的影响 我们的CPSI表达克隆的突变体。除了研究 这种多态的功能特征，我将确定是否 CPSI基因与毒性之间有任何关联 在接受骨髓移植的患者中观察。作为与我合作的一部分 布莱恩·克里斯曼博士，我们观察到尿素循环的显著变化 骨髓移植诱导化疗后的中间体，并有 初步数据显示与CPSI多态不平衡。我们 将进一步测试CPSI多态基因型之间的相关性 患者存在观察到的生化/临床毒性 开始丙戊酸治疗。我们还将筛查CPSI基因 其他可检测的外显子多态。我们将建立 这些常见的多态在尿素循环相关基因中的作用 在这些患者身上看到了毒性。这项研究的积极结果将 导致进一步研究涉及错乱的其他条件 废氮处理。

The molecular study of defects in ammonia metabolism has been generally limited to rare inborn errors of metabolism. Hyperammonemia, however, is much more common and is associated with non-genetic conditions and environmental exposures. These conditions usually involve some degree of physical hepatic damage or disruption. A common example is the frequent hyperammonemia observed in patients following administration of the drug valproic acid. With the increase in bone marrow transplant procedures (BMT), a number of hyperammonemic deaths have been reported. In addition, more subtle toxicities may result from mild increases in urea cycle precursors (glutamine, alanine, glycine, etc.), or decreases in urea cycle intermediates (arginine and citrulline). Whatever the triggering event, disturbances in ammonia clearance reflect physical or biochemical effects on the urea cycle. My research has focused on characterizing the gene encoding the first, rate-limiting step of ureagenesis, carbamyl phosphate synthetase I (CPSI). In patient studies, I have found a number of rare CPSI molecular defects resulting in severe inherited disruptions of the urea cycle. During these studies, I have also identified a common exonic polymorphism which may qualitatively affect CPSI function. This study is designed to examine the clinical and biochemical significance of this polymorphism and identify other potentially relevant changes in the CPSI gene. These changes may play a key role in the susceptibility to urea cycle toxicity secondary to drug or toxin exposure. I will study the functional affects of this change on expressed CPSI protein using site-directed mutants of our CPSI expression clone. In addition to studying the functional characteristics of this polymorphism, I will determine if there is any association between the CPSI genotype and the toxicity observed in patients undergoing BMT. As part of my collaboration with Dr. Brian Christman, we have observed significant changes in urea cycle intermediates following induction chemotherapy for BMT, and have preliminary data showing disequilibrium with the CPSI polymorphism. We will further test the correlation between the CPSI polymorphic genotypes with the presence of observed biochemical/clinical toxicity in patients beginning therapy with valproic acid. We will also screen the CPSI gene for other exonic polymorphisms which can be tested. We will establish the role of these common polymorphisms in the urea-cycle related toxicity seen in these patients. Positive results in this study will lead to further study of other conditions involving the derangement of waste nitrogen disposal.