Influence of genotype on urinary oxalate excretion

描述(由申请人提供)： 原发性高草酸尿症是指乙醛代谢异常，表现为草酸的大量产生和尿液排泄，草酸钙肾结石复发和肾功能衰竭。目前已报道了多种致病酶(PHI中的丙氨酸：乙醛酸氨基转移酶或AGT，PHII中的乙醛：羟丙酮酸还原酶或GR/HPR)的突变，但目前尚缺乏基因和表型之间的临床相关性。梅奥诊所是PH的第三转诊中心，拥有数十年广泛的诊断、治疗和长期临床随访经验，世界上最大的PH患者队列之一在一个医疗中心进行跟踪。虽然PH很少见，但特发性草酸钙肾结石非常常见，轻度高草酸尿症似乎是许多受影响患者的重要致病因素。因此，加深对饮食和草酸产生代谢途径相互作用的了解，例如AGT的作用，可能会导致对肾结石发病机制的重要见解。申请人在过去4年致力于高草酸血症分子遗传学的深入研究，包括在伦敦大学学院(UCL)担任梅奥基金会学者2年。梅奥大学和伦敦大学学院成立了一个致力于临床和研究指导的小组，以促进三个特定目标的成功完成，这些目标旨在严格定义特定突变和多态对高草酸状态草酸排泄和临床表型的影响。(1)变性高效液相色谱将被用于有效地筛选具有良好特征的PH患者的Mayo队列，以寻找描述的和新的突变以及多态。(2)所有新描述的突变都将在体外表达，以研究它们的功能并验证它们的致病潜力。(3)在一组特发性草酸钙结石患者中，将明确AGT基因的正常等位基因变异对尿草酸排泄和吡哆醇反应性的影响。申请者的长期目标是建立一个研究性的最先进的实验室，致力于研究高草酸尿的分子遗传学。

DESCRIPTION (provided by applicant): The primary hyperoxalurias (PH) are inbom errors of glyoxylate metabolism characterized by excessive production and urinary excretion of oxalate, recurrent calcium oxalate nephrolithiasis and renal failure. A number of mutations have been described in the causative enzymes (alanine:glyoxylate aminotransferase or AGT in PHI, and glyoxylate:hydroxypyruvate reductase or GR/HPR in PHII) but clinically relevant correlations between genotype and phenotype are currently lacking. The Mayo Clinic serves as a tertiary referral center for PH and has decades of extensive diagnostic, therapeutic, and long-term clinical follow-up experience, with one of the largest PH patient cohorts followed at a single medical center in the world. Although PH is rare, idiopathic calcium oxalate nephrolithiasis is extremely common, and mild hyperoxaluria appears to be an important pathogenic factor in many affected patients. Therefore, increased understanding regarding the interaction of diet and metabolic pathways of oxalate production, e.g. the role of AGT, could lead to important insights regarding renal stone pathogenesis. The applicant has devoted the last 4 years to intensive study of the molecular genetics of hyperoxaluria, including 2 years as a Mayo Foundation Scholar at University College London (UCL). A committed group of clinical and research mentors, both at Mayo and UCL, has been established to facilitate successful completion of 3 Specific Aims that are designed to rigorously define the effect of specific mutations and polymorphisms on oxalate excretion and clinical phenotype in hyperoxaluric states. (1) Denaturing high-performance liquid chromatography will be employed to efficiently screen the well-characterised Mayo cohort of PH patients for described and novel mutations, as well as polymorphisms. (2) All newly-described mutations will be expressed to study their function in vitro and verify their disease-causing potential. (3) The effect of normal allelic variation at the AGT locus on urine oxalate excretion and pyridoxine responsiveness will be defined in a group of idiopathic calcium oxalate stone formers. The applicant's long-term objective is to establish an investigative state-of the- art laboratory devoted to the study of the molecular genetics of hyperoxaluria.