Alternative titles; symbols
HGNC Approved Gene Symbol: GRHPR
SNOMEDCT: 40951006;
Cytogenetic location: 9p13.2 Genomic coordinates (GRCh38): 9:37,422,435-37,439,494 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.2 | Hyperoxaluria, primary, type II | 260000 | Autosomal recessive | 3 |
Cramer et al. (1999) and Rumsby and Cregeen (1999) independently identified a glyoxylate reductase/hydroxypyruvate reductase (GRHPR; EC 1.1.1.79) cDNA clone from a human liver EST library. The GRHPR gene encodes a predicted 328-amino acid protein with a calculated molecular mass of 35.5 kD. By transient transfection of the cDNA clone into COS cells, Cramer et al. (1999) verified that GRHPR encodes an enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate dehydrogenase enzymatic activities. Database analysis of human ESTs revealed widespread tissue expression, indicating that the enzyme may have a role in metabolism.
Cramer et al. (1999) determined that the GRHPR gene contains 9 exons spanning approximately 9 kb.
Using ESTs, Cramer et al. (1999) found that the GRHPR gene maps pericentromeric on chromosome 9. Webster et al. (2000) presented haplotype data indicating that the GRHPR gene is located near the marker D9S1874.
In 2 pairs of sibs from 2 unrelated families with type II hyperoxaluria (260000), Cramer et al. (1999) identified a 1-bp deletion in the GRHPR gene (103delG; 604296.0001) by SSCP analysis. All 4 patients were homozygous for the same mutation.
Webster et al. (2000) identified 5 other mutations in patients with type II hyperoxaluria. Ten of 11 patients that they had genotyped were homozygous for 1 of the 6 known mutations. In the case of two-thirds of the patients, the parents were related. Genotyping also showed the possible presence of a founder effect for the 2 most common mutations: 103delG and arg99 to ter (R99X; 604296.0002).
In 4 Japanese patients with HP2, Takayama et al. (2014) identified homozygous or compound heterozygous mutations in the GRHPR gene (604296.0003-604296.0005). Three of the patients were homozygous for the same mutation (c.864delTG; 604296.0003).
In 2 pairs of sibs from 2 unrelated families with type II primary hyperoxaluria (HP2; 260000), Cramer et al. (1999) identified deletion of the first nucleotide (G) of codon 35 (103G) of the GRHPR gene, resulting in a frameshift beginning at codon 35 and predicted to result in a truncated protein of 44 amino acids. All 4 patients were homozygous for this mutation.
The c.103delG mutation in exon 2 results in a frameshift and premature termination (Asp35ThrfsTer44). It is the most common GRHPR mutation, occurring in approximately 40% of published cases, and is found only in Caucasian individuals of northern European or American origin (review by Takayama et al., 2014).
In 4 of 18 alleles of the GRHPR gene in patients with type II primary hyperoxaluria (HP2; 260000), Webster et al. (2000) found a 295C-T transition causing a nonsense arg99-to-ter (R99X) amino acid substitution.
In 3 unrelated Japanese patients with type II primary hyperoxaluria (HP2; 260000), Takayama et al. (2014) identified a homozygous 2-bp deletion (c.864_865delTG) in exon 8 of the GRHPR gene, resulting in a frameshift and premature termination. The mutation was not found in 474 Japanese control alleles.
In a Japanese patient with type II primary hyperoxaluria (HP2; 260000), Takayama et al. (2014) identified compound heterozygous mutations in the GRHPR gene: a 2-bp deletion in exon 3 (c.248_249delTG), resulting in a frameshift and premature termination at codon 91, and a c.904C-T transition in exon 9, resulting in an arg302-to-cys (R302C; 604296.0005) substitution. The R302C mutant has 5.6% residual enzymatic activity (Cregeen et al., 2003).
For discussion of the arg302-to-cys (R302C) mutation in the GRHPR gene that was found in compound heterozygous state in a patient with type II primary hyperoxaluria (HP2; 260000) by Takayama et al. (2014), see 604296.0004.
Cramer, S. D., Ferree, P. M., Lin, K., Milliner, D. S., Holmes, R. P. The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum. Molec. Genet. 8: 2063-2069, 1999. Note: Erratum: Hum. Molec. Genet. 8: 2574 only, 1999. [PubMed: 10484776] [Full Text: https://doi.org/10.1093/hmg/8.11.2063]
Cregeen, D. P., Williams, E. L., Hulton, S., Rumsby, G. Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2. (Abstract) Hum. Mutat. 22: 497 only, 2003. [PubMed: 14635115] [Full Text: https://doi.org/10.1002/humu.9200]
Rumsby, G., Cregeen, D. P. Identification and expression of a cDNA for human hydroxypyruvate/glyoxylate reductase. Biochim. Biophys. Acta 1446: 383-388, 1999. [PubMed: 10524214] [Full Text: https://doi.org/10.1016/s0167-4781(99)00105-0]
Takayama, T., Takaoka, N., Nagata, M., Johnin, K., Okada, Y., Tanaka, S., Kawamura, M., Inokuchi, T., Ohse, M., Kuhara, T., Tanioka, F., Yamada, H., Sugimura, H., Ozono, S. Ethnic differences in GRHPR mutations in patients with primary hyperoxaluria type 2. Clin. Genet. 86: 342-348, 2014. [PubMed: 24116921] [Full Text: https://doi.org/10.1111/cge.12292]
Webster, K. E., Ferree, P. M., Holmes, R. P., Cramer, S. D. Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2). Hum. Genet. 107: 176-185, 2000. [PubMed: 11030416] [Full Text: https://doi.org/10.1007/s004390000351]