Human Molecular Genetics, Vol 8, 2063-2069, Copyright © 1999 by Oxford University Press
SD Cramer, PM Ferree, K Lin, DS Milliner and RP Holmes
Primary hyperoxaluria type II (PH2) is a rare monogenic disorder that is
characterized by a lack of the enzyme that catalyzes the reduction of
hydroxypyruvate to D-glycerate, the reduction of glyoxylate to glycolate
and the oxidation of D-glycerate to hydroxypyruvate. The disease is
characterized by an elevated urinary excretion of oxalate and L-glycerate.
The increased oxalate excretion can cause nephrolithiasis and nephrocalci-
nosis and can, in some cases, result in renal failure and systemic oxalate
deposition. We identified a glyoxylate reductase/hydroxypyruvate reductase
(GRHPR) cDNA clone from a human liver expressed sequence tag (EST) library.
Nucleotide sequence analysis identified a 1198 nucleotide clone that
encoded a 984 nucleotide open reading frame. The open reading frame encodes
a predicted 328 amino acid protein with a mass of 35 563 Da. Transient
transfection of the cDNA clone into COS cells verified that it encoded an
enzyme with hydroxy- -pyruvate reductase, glyoxylate reductase and D-
glycerate dehydrogenase enzymatic activities. Database analysis of human
ESTs reveals widespread tissue expression, indicating that the enzyme may
have a previously unrecognized role in metabolism. The genomic structure of
the human GRHPR gene was determined and contains nine exons and eight
introns and spans approximately 9 kb pericentromeric on chromosome 9. Four
PH2 patients representing two pairs of siblings from two unrelated families
were analyzed for mutations in GRHPR by single strand conformation
polymorphism analysis. All four patients were homozygous for a single
nucleotide deletion at codon 35 in exon 2, resulting in a premature stop
codon at codon 45. The cDNA that we have identified represents the first
characterization of an animal GRHPR sequence. The data we present will
facilitate future genetic testing to confirm the clinical diagnosis of PH2.
These data will also facilitate heterozygote testing and prenatal testing
in families affected with PH2 to aid in genetic counseling.
ARTICLES
The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II
Department of Cancer Biology,
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