Influence of genotype on urinary oxalate excretion

描述（由申请人提供）： 原发性高尿酸血症（PH）是乙醛酸代谢异常，以草酸盐过量产生和排泄、反复发作的草酸钙肾结石和肾功能衰竭为特征。在致病酶中已经描述了许多突变（PHI中的丙氨酸：乙醛酸氨基转移酶或AGT，以及PHII中的乙醛酸：羟基丙酮酸还原酶或GR/HPR），但目前缺乏基因型和表型之间的临床相关性。马约诊所是PH的三级转诊中心，拥有数十年的广泛诊断、治疗和长期临床随访经验，是世界上最大的PH患者队列之一。虽然PH是罕见的，但特发性草酸钙肾结石是非常常见的，轻度高尿酸似乎是许多患者的重要致病因素。因此，对饮食和草酸盐生成代谢途径的相互作用（例如AGT的作用）的了解增加，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年中致力于高尿酸分子遗传学的深入研究，包括在伦敦大学学院（UCL）担任马约基金会学者2年。马约和UCL的临床和研究导师团队已经成立，以促进成功完成3个特定目标，旨在严格定义特定突变和多态性对高尿酸状态下草酸排泄和临床表型的影响。(1)变性高效液相色谱法将被用来有效地筛选表征良好的马约PH患者队列中描述的和新的突变，以及多态性。(2)所有新描述的突变都将被表达，以研究它们的体外功能并验证它们的致病潜力。(3)AGT基因座正常等位基因变异对尿草酸排泄和吡哆醇反应性的影响将在一组特发性草酸钙结石形成者中确定。申请人的长期目标是建立一个最先进的研究实验室，专门研究高尿酸的分子遗传学。

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.