The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in primary hyperoxaluria type II

Wake Forest University, Winston-Salem, North Carolina, United States
Human Molecular Genetics (Impact Factor: 6.39). 11/1999; 8(11):2063-9. DOI: 10.1093/hmg/8.11.2063
Source: PubMed


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.

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Available from: Patrick M Ferree, Feb 16, 2014
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    • "Calcium oxalate crystallizes in the urine, leading to nephrocalcinosis , urolithiasis, and consequent renal failure if treatment is not initiated promptly. The three known types of PH are PH1, due to mutations in the AGXT gene (Purdue et al. 1990), PH2, caused by mutations in GRHPR (Cramer et al. 1999), and PH3 arising from defects in HOGA1 (Belostotsky et al. 2010). The different types of PH appear clinically very similar, with a similar age of onset (Williams et al. 2012) although treatment choices vary according to type, and it is, therefore, essential that an accurate diagnosis is established early in the course of disease to guide appropriate and effective treat- ment. "
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    ABSTRACT: Definitive diagnosis of primary hyperoxaluria (PH) currently utilizes sequential Sanger sequencing of the AGXT, GRPHR, and HOGA1 genes but efficacy is unproven. This analysis is time-consuming, relatively expensive, and delays in diagnosis and inappropriate treatment can occur if not pursued early in the diagnostic work-up. We reviewed testing outcomes of Sanger sequencing in 200 consecutive patient samples referred for analysis. In addition, the Illumina Truseq custom amplicon system was evaluated for paralleled next-generation sequencing (NGS) of AGXT, GRHPR, and HOGA1 in 90 known PH patients. AGXT sequencing was requested in all patients, permitting a diagnosis of PH1 in 50%. All remaining patients underwent targeted exon sequencing of GRHPR and HOGA1 with 8% diagnosed with PH2 and 8% with PH3. Complete sequencing of both GRHPR and HOGA1 was not requested in 25% of patients referred leaving their diagnosis in doubt. NGS analysis showed 98% agreement with Sanger sequencing and both approaches had 100% diagnostic specificity. Diagnostic sensitivity of Sanger sequencing was 98% and for NGS it was 97%. NGS has comparable diagnostic performance to Sanger sequencing for the diagnosis of PH and, if implemented, would screen for all forms of PH simultaneously ensuring prompt diagnosis at decreased cost.
    Full-text · Article · Nov 2014
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    • "The second type, PH2 (MIM #260000), is caused by a deficiency in glyoxylate reductase/hydroxypyruvate reductase (GRHPR; EC [3] [4] [5], a cytosolic enzyme. The recently identified PH type 3 (MIM #613616) [6] is linked to the gene DHDPSL, encoding a mitochondrial enzyme, although "
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    ABSTRACT: Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxylate and oxalate. PH type 1, the most common form, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine, glyoxylate aminotransferase (AGT) resulting in overproduction and excessive urinary excretion of oxalate. Recurrent urolithiasis and nephrocalcinosis are the hallmarks of the disease. As glomerular filtration rate decreases due to progressive renal damage, oxalate accumulates leading to systemic oxalosis. Diagnosis is often delayed and is based on clinical and sonographic findings, urinary oxalate assessment, DNA analysis, and, if necessary, direct AGT activity measurement in liver biopsy tissue. Early initiation of conservative treatment, including high fluid intake, inhibitors of calcium oxalate crystallization, and pyridoxine in responsive cases, can help to maintain renal function in compliant subjects. In end-stage renal disease patients, the best outcomes have been achieved with combined liver-kidney transplantation which corrects the enzyme defect.
    Full-text · Article · Jun 2011
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    • "Primary hyperoxaluria (PH) is a rare but potentially fatal inherited disease in humans resulting from mutations in the alanine:glyoxylate aminotransferase (AGT ) gene (type I or PH1) or in the glyoxylate reductase (GRHPR) gene (type II or PH2)(Purdue et al. 1990; Cramer et al. 1999; Cregeen et al. 2003). Biochemically, the disease in humans is characterized by decreased hepatic AGT, or GRHPR enzyme activity in type I or type II disease, respectively, increased urinary concentrations of oxalate in both types, as well as increased urinary concentrations of L-glyceric acid in type II. "
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    ABSTRACT: Primary hyperoxaluria (PH) is a rare, inherited disease in humans resulting from mutations in the alanine:glyoxylate aminotransferase gene (PH1) or in the glyoxylate reductase (GRHPR) gene (PH2). A disease in cats, mimicking PH2, was described with an autosomal recessive mode of inheritance. Recently, we recognized lesions consistent with PH in kidneys from 3 kittens. Genomic DNA was extracted from 1 blood and 2 formalin-fixed kidney samples from the 3 affected kittens, from blood from the affected cats’ sire, and from blood from 2 healthy unrelated cats. The 9 feline GRHPR exons and intronic donor–acceptor sites were amplified and sequenced. A point mutation G to A was identified at the acceptor site of intron 4. Affected cats were AA, normal cats GG, and the sire was heterozygous A/G. RNA from healthy, carrier, and affected cats was extracted and the GRHPR transcript sequenced revealing an exon 5 deletion in the affected transcript. The 89-bp deletion causes a frameshift and a premature stop codon 44 amino acids downstream, resulting in an anticipated 119 amino acids missing from the C-terminus of the affected cat protein. The unaffected cat expresses the normal transcript, whereas the carrier expressed both.
    Preview · Article · Jul 2009 · The Journal of heredity
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