Alternative titles; symbols
HGNC Approved Gene Symbol: GMPR
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38): 6:16,238,587-16,295,549 (from NCBI)
Guanosine monophosphate reductase (EC 1.7.1.7) catalyzes the irreversible NADPH-dependent reductive deamination of guanosine monophosphate (GMP) to inosine monophosphate (IMP). GMPR is able to convert guanosine nucleotides to the pivotal precursor of both guanine (G) and adenine (A) nucleotides. It plays an important role in maintaining the intracellular balance of A and G nucleotides.
Beutler et al. (1990) and Mason et al. (1990) presented evidence that a gene mapped to chromosome 6 by Kanno et al. (1989) was GMP reductase. Henikoff and Smith (1989) had pointed out similarities between the sequence described by Kanno et al. (1989) for the chromosome 6-encoded gene and the sequence of E. coli GMP reductase. Kondoh et al. (1991) found that the GMPR gene encodes a deduced 345-amino acid protein.
By Northern blot analysis, Deng et al. (2002) detected relatively high levels of both GMPR1 and GMPR2 (610781) in heart, skeletal muscle, and kidney, and relatively low levels of both in colon, thymus, and peripheral blood leukocyte. Strong signals of GMPR2 were detected in brain, liver, and placenta, whereas weak signals of GMPR1 were observed in these tissues.
Kondoh et al. (1991) determined that the GMPR gene spans about 50 kb and contains 9 exons. The gene contains 2 potential Sp1 binding sites within exon 1, and a functional, atypical polyadenylation signal in exon 9.
By fluorescence in situ hybridization, Murano et al. (1994) mapped the GMPR gene to chromosome 6p23.
Associations Pending Confirmation
Sommerville et al. (2020) described a 73-year-old woman with a medical history significant for late adult-onset progressive ophthalmoplegia (PEO; see 157640). At age 60, she underwent surgery for strabismus, and at 69, she developed mild bilateral ptosis, marked PEO, and mild facial and proximal muscle weakness. A muscle biopsy showed approximately 15% cytochrome c oxidase-deficient muscle fibers and occasional ragged-red fibers. Long-range PCR showed multiple mtDNA deletions, which was confirmed by single-fiber real-time PCR. Whole-exome sequencing identified a novel heterozygous c.547G-C transversion (NM_006877.3) in exon 5 of the GMPR gene, which was confirmed by Sanger sequencing. The mutation was not present in the gnomAD database or in an in-house database of 378 controls. Studies in patient fibroblasts showed that the mutation likely leads to skipping of exon 5, ultimately resulting in a frameshift and premature termination (Ala156ValfsTer17) that would be subject to nonsense-mediated decay. Immunoblotting in patient muscle tissue showed decreased GMPR protein expression. Further studies in patient muscle also showed decreased pyrimidine nucleotide carrier-1 (610816) protein levels and mild increases in the large R1 subunit of ribonucleotide reductase, indicating potential effects on the machinery of nucleotide homeostasis. Sommerville et al. (2020) proposed that GMPR represents an important nuclear-encoded gene associated with PEO and multiple mtDNA deletions.
Kanno et al. (1989) suggested that red cell G6PD (305900) is a fusion protein consisting of an NH2-terminus encoded by chromosome 6 and a COOH-portion coded by an X chromosome. This was subsequently disproved by Beutler et al. (1990) and by Mason et al. (1990).
Kondoh et al. (1991) identified a T-to-A substitution at nucleotide 766 of the GMPR gene resulting in substitution of isoleucine for phenylalanine at amino acid residue 256 in the variant protein. The frequency of the ile256 variant was thought to be about 30%. A silent C-to-T change at codon 630 was also found, with a frequency of about 10%; the silent change created an additional restriction cleavage site.
Beutler, E., Gelbart, T., Kuhl, W. Human red cell glucose-6-phosphate dehydrogenase: all active enzyme has sequence predicted by the X chromosome-encoded cDNA. Cell 62: 7-9, 1990. [PubMed: 2364435] [Full Text: https://doi.org/10.1016/0092-8674(90)90231-3]
Deng, Y., Wang, Z., Ying, K., Gu, S., Ji, C., Huang, Y., Gu, X., Wang, Y., Xu, Y., Li, Y., Xie, Y., Mao, Y. NADPH-dependent GMP reductase isoenzyme of human (GMPR2): expression, purification, and kinetic properties. Int. J. Biochem. Cell Biol. 34: 1035-1050, 2002. [PubMed: 12009299] [Full Text: https://doi.org/10.1016/s1357-2725(02)00024-9]
Henikoff, S., Smith, J. M. The human mRNA that provides the N-terminus of chimeric G6PD encodes GMP reductase. Cell 58: 1021-1022, 1989. [PubMed: 2570640] [Full Text: https://doi.org/10.1016/0092-8674(89)90498-4]
Kanno, H., Huang, I.-Y., Kan, Y. W., Yoshida, A. Two structural genes on different chromosomes are required for encoding the major subunit of human red cell glucose-6-phosphate dehydrogenase. Cell 58: 595-606, 1989. [PubMed: 2758468] [Full Text: https://doi.org/10.1016/0092-8674(89)90440-6]
Kondoh, T., Kanno, H., Chang, L., Yoshida, A. Genomic structure and expression of human guanosine monophosphate reductase. Hum. Genet. 88: 219-224, 1991. [PubMed: 1661705] [Full Text: https://doi.org/10.1007/BF00206076]
Kondoh, T., Kanno, H., Chang, L., Yoshida, A. Identification of common variant alleles of the human guanosine monophosphate reductase gene. Hum. Genet. 88: 225-227, 1991. [PubMed: 1757097] [Full Text: https://doi.org/10.1007/BF00206077]
Mason, P. J., Bautista, J. M., Vulliamy, T. J., Turner, N., Luzzatto, L. Human red cell glucose-6-phosphate dehydrogenase is encoded only on the X chromosome. Cell 62: 9-10, 1990. [PubMed: 2194676] [Full Text: https://doi.org/10.1016/0092-8674(90)90232-4]
Murano, I., Tsukahara, M., Kajii, T., Yoshida, A. Mapping of the human guanosine monophosphate reductase gene (GMPR) to chromosome 6p23 by fluorescence in situ hybridization. Genomics 19: 179-180, 1994. [PubMed: 8188226] [Full Text: https://doi.org/10.1006/geno.1994.1036]
Sommerville, E. W., Dalla Rosa, I., Rosenberg, M. M., Bruni, F., Thompson, K., Rocha, M., Blakely, E. L., He, L., Falkous, G., Schaefer, A. M., Yu-Wai-Man, P., Chinnery, P. F., Hedstrom, L., Spinazzola, A., Taylor, R. W., Gorman, G. S. Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance. Clin. Genet. 97: 276-286, 2020. [PubMed: 31600844] [Full Text: https://doi.org/10.1111/cge.13652]
Yoshida, A., Kan, Y. W. Origin of 'fused' glucose-6-phosphate dehydrogenase. Cell 62: 11-12, 1990. [PubMed: 1694726] [Full Text: https://doi.org/10.1016/0092-8674(90)90233-5]