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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Rankin, Tracy L
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Mayo Clinic, Rochester
United States
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Monico, Carla G; Weinstein, Adam; Jiang, Zhirong et al. (2008) Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis. Am J Kidney Dis 52:1096-103
Monico, Carla G; Rossetti, Sandro; Schwanz, Heidi A et al. (2007) Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis. J Am Soc Nephrol 18:1905-14
Monico, Carla G; Rossetti, Sandro; Olson, Julie B et al. (2005) Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 67:1704-9
Monico, Carla G; Olson, Julie B; Milliner, Dawn S (2005) Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria. Am J Nephrol 25:183-8