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

Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Human Molecular Genetics (Impact Factor: 6.68). 11/1999; 8(11):2063-9. DOI: 10.1093/hmg/8.11.2063
Source: PubMed

ABSTRACT 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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    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.
    Molecular Genetics & Genomic Medicine. 11/2014; 3(1).
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    ABSTRACT: Background The olive mouse Abrothrix olivacea is a cricetid rodent of the subfamily Sigmodontinae that inhabits a wide range of contrasting environments in southern South America, from aridlands to temperate rainforests. Along its distribution, it presents different geographic forms that make the olive mouse a good focal case for the study of geographical variation in response to environmental variation. We chose to characterize the kidney transcriptome because this organ has been shown to be associated with multiple physiological processes, including water reabsorption. Results Transcriptomes of thirteen kidneys from individuals from Argentina and Chile were sequenced using Illumina technology in order to obtain a kidney reference transcriptome. After combine the reads produced for each sample, we explored three assembly strategies to obtain the best reconstruction of transcripts, TrinityNorm and DigiNorm, which each one applied its own normalization algorithm for redundant reads removal, and Multireads, which simply consist on the assembly of the joined reads. We found that multireads strategy produces a less fragmented assembly than normalization counterparts but recover fewer number of genes. In general, about 15000 genes were annotated, of which almost half had at least one coding sequence reconstructed at 99% of its length. We also built a list of highly expressed genes, of which several are involved in water conservation under laboratory conditions using mouse models. Conclusion Based on our assembly results, Trinity's in silico normalization is the best algorithm in terms of cost-benefit returns; however, our results also indicate that normalization should be avoided if the complete or nearly complete coding sequences of genes are desired. Given that this work is the first to characterize the transcriptome of any member of Sigmodontinae, a subfamily of cricetid rodents with about 400 living species, it will provide valuable resources for future ecological and evolutionary genomic analyses.
    BMC Genomics 06/2014; 15:446. · 4.04 Impact Factor

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