title: Hydroxyproline metabolism in a mouse model of Primary Hyperoxaluria Type 3.
abstract: Primary Hyperoxaluria Type 3 is a recently discovered form of this autosomal recessive disease that results from mutations in the gene coding for 4-hydroxy-2-oxoglutarate aldolase (HOGA1). This enzyme is one of the 2 unique enzymes in the hydroxyproline catabolism pathway. Affected individuals have increased urinary excretions of oxalate, 4-hydroxy-L-glutamate (4-OH-Glu), 4-hydroxy-2-oxoglutarate (HOG), and 2,4-dihydroxyglutarate (DHG). While 4-OH-Glu and HOG are precursor substrates of HOGA1 and increases in their concentrations are expected, how DHG is formed and how HOG to oxalate are unclear. To resolve these important questions and to provide insight into possible therapeutic avenues for treating this disease, an animal model of the disease would be invaluable. We have developed a mouse model of this disease which has null mutations in the Hoga1 gene and have characterized its phenotype. It shares many characteristics of the human disease, particularly when challenged by the inclusion of hydroxyproline in the diet. An increased oxalate excretion is not observed in the KO mice which may be consistent with the recent recognition that only a small fraction of the individuals with the genotype for HOGA deficiency develop PH.
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Xingsheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: John
authors.initials: J
authors.lastname: Knight
authors.affiliation: Department of Biochemistry, Center for Structural Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA.
authors.forename: W
authors.initials: W
authors.lastname: Todd Lowther
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: rholmes@uab.edu.
authors.forename: Ross P
authors.initials: RP
authors.lastname: Holmes
keywords: Hydroxyproline; Mouse model; Oxalate; Primary Hyperoxaluria