Identification and expression of a cDNA for human hydroxypyruvate/glyoxylate reductase

Rumsby, Gill; Cregeen, David

doi:10.1016/s0167-4781(99)00105-0

Cited by 47 publications

(26 citation statements)

References 8 publications

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“…The Aspartate165 mutation has previously been documented with respect to deficient D-glycerate dehydrogenase activity (Webster et al, 2000). Glycine 165 is the terminal residue within the putative cofactor binding site, sequence GXGXXG, which is highly conserved between GR enzymes from different species (Rumsby and Cregeen, 1999). The sequence creates a tight turn between the end of the β sheet and the beginning of the following α helix (Taguchi and Ohta, 1991) thus substitution of the neutral glycine residue with a negatively charged aspartate is likely to affect folding and cofactor binding to the protein; in vitro expression confirmed that an unstable protein with greatly reduced catalytic activity was produced.…”

Section: Discussionmentioning

confidence: 99%

“…Urine oxalate excretion is elevated to a similar degree to that seen in primary hyperoxaluria type 1, but renal failure tends to occur later (Milliner et al, 2001;Johnson et al, 2002). PH2 is caused by mutations in the GRHPR gene (MIM# 604296), which encodes a protein with glyoxylate reductase (GR, EC1.1.1.26/79) and hydroxypyruvate reductase (HPR) activities (Cramer et al, 1999;Rumsby and Cregeen, 1999). This cytosolic enzyme plays a role in the metabolism of glyoxylate and in the production of gluconeogenic precursors from serine via hydroxypyruvate.…”

Section: Introductionmentioning

confidence: 99%

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Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2

et al. 2003

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Primary hyperoxaluria type 2, an inherited autosomal recessive disorder of endogenous oxalate overproduction, is caused by mutations in the GRHPRIn addition, a splice variant lacking 28 bp of exon 1 was expressed in a number of tissues but is of unknown function. Two polymorphisms, c.579A>G in exon 6 and a (CT) n microsatellite in intron 8 were identified. Expression studies showed that the G165D and R302C mutants had glyoxylate reductase activity 1.5 and 5.6% respectively of the wild type protein. Both mutant proteins were unstable on purification. Although there is wide expression of the GRHPR mRNA demonstrated by northern blot analysis, our study shows that GRHPR protein distribution is predominantly hepatic and concludes that PH2, like the related type 1 disease, is primarily a disorder affecting hepatic glyoxylate metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2

et al. 2003

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“…Confirmation of the diagnosis of PH2 can be made by measuring GR activity in hepatic biopsy samples [4]. The human gene encoding GR (termed the GRHPR gene) has been mapped to chromosome 9 and contains nine exons, spanning 9 kilobases [6,7]. Several mutations have been identified [7,8], allowing molecular diagnostics to be used.…”

Section: Introductionmentioning

confidence: 99%

Primary hyperoxaluria type 2 in children

et al. 2002

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The primary hyperoxalurias (PH1 and PH2) are rare defects of oxalate overproduction. There are only 24 reported cases of PH2, which is characterized by raised urine oxalate and L-glycerate. We describe 13 previously unreported children with PH2, representing the largest single-centre cohort in the world. DNA samples were tested for a common mutation and four other documented mutations in the gene encoding the enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). Two of the five kindred showed homozygosity for two different mutations in the GRHPR gene. The genetic defect was not identified in the other three families. The median age at diagnosis of PH2 was 1.7 years. Five children presented with nephrolithiasis between 0.8 and 9 years. Haematuria was common, but urinary tract infection and nephrocalcinosis were not. All had normal renal function at diagnosis, and only 1 patient had a significant decline in glomerular filtration rate. We conclude that all children with nephrolithiasis secondary to hyperoxaluria should have urinary glycerate measured, as PH2 may be more prevalent than currently estimated. DNA mutational analysis may be useful in supporting the diagnosis.

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“…The open reading frame translates to a predicted 328-amino-acid protein with a predicted mass of 35,563 Da. Another group has identified an identical cDNA with HPR and GR activities, encoding a 328-amino-acid protein (Rumsby and Cregeen 1999). We have recently determined the genomic structure of the GRHPR gene and demonstrated that it contains nine exons and eight introns spanning approximately 9 kb pericentromeric on chromosome 9, within the reference interval D9S1874-D9S273 (Cramer et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2)

et al. 2000

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Primary hyperoxaluria type II (PH2) is a rare disease characterized by the absence of an enzyme with glyoxylate reductase, hydroxypyruvate reductase, and D-glycerate dehydrogenase activities. The gene encoding this enzyme (GRHPR) has been characterized, and a single mutation has been detected in four PH2 patients. In this report, we have identified five novel mutations. One nonsense mutation (C295T) results in a premature stop codon at codon 99. A 4-bp deletion mutation has been found in the 5' consensus splice site of intron D, resulting in a predicted splicing error. Three missense mutations have been detected, including a missense transversion (T965G) in exon 9 (Met322Arg), a missense transition (G494A) in the putative co-factor binding site in exon 6 (Gly165Asp), and a substitution of an adenosine for a guanine in the 3' splice site of intron G. The functional consequences of the missense transversion and transition mutations have been investigated by transfection of cDNA encoding the mutated protein into COS cells. Cells transfected with either mutant construct have no enzymatic activity, a finding that is not significantly different from the control (empty) vector (P<0.05). These results further confirm that mutations in the GRHPR gene form the genetic basis of PH2. Ten of the 11 patients that we have genotyped are homozygous for one of the six mutations identified to date. Because of this high proportion of homozygotes, we have used microsatellite markers in close linkage with the GRHPR gene to investigate the possibility that the patients are the offspring of related individuals. Our data suggest that two thirds of our patients are the offspring of either closely or distantly related persons. Furthermore, genotyping has revealed the possible presence of a founder effect for the two most common mutations and the location of the gene near the marker D9S1874.

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Identification and expression of a cDNA for human hydroxypyruvate/glyoxylate reductase

Cited by 47 publications

References 8 publications

Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2

Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2

Primary hyperoxaluria type 2 in children

Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2)

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