Alternative titles; symbols
HGNC Approved Gene Symbol: RRM1
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:4,094,685-4,138,932 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 6 | 620647 | Autosomal dominant; Autosomal recessive | 3 |
The RRM1 gene encodes the large subunit (R1) of ribonucleotide reductase, the heterodimeric enzyme that catalyzes the rate-limiting step for the production of deoxyribonucleotides needed for DNA synthesis (summary by Pavloff et al., 1992).
Pavloff et al. (1992) cloned human RRM1 and RRM2 (180390) cDNAs from a breast carcinoma cDNA library. The deduced 792-amino acid RRM1 protein has a molecular mass of 90 kD and shares about 98% sequence homology with the mouse Rrm1 protein.
By immunoblotting of somatic cell hybrid extracts, Engstrom and Francke (1985) mapped the gene for the R1 subunit of ribonucleotide reductase to 11pter-p11. This assignment was confirmed by Southern analysis of hybrid cell DNAs, and the RRM1 locus was sublocalized to the distal band 11p15 by in situ hybridization (Brissenden et al., 1988).
Byrne and Smith (1991) identified a RFLP at the RRM1 locus.
Parker et al. (1994) used a fragment of human RRM1 cDNA to isolate a genomic clone that encompassed the 5-prime flanking region of RRM1. Primer extension and PCR experiments defined 6 potential cap sites.
Parker et al. (1995) characterized the TATA-less promoter region of the human RRM1 gene and found 2 domains that were conserved with respect to the mouse sequence. One of these sequences was shown to bind the transcription factor SP1 (189906).
Pitterle et al. (1999) demonstrated that the RRM1 gene contains 19 exons, spans over 45 kb, and is oriented from telomere to centromere with exon 19 nearest to D11S12.
In dividing cells, ribonucleotide reductase is essential for the production of deoxyribonucleotides before DNA synthesis in S phase. Neither of its 2 subunits, R1 or R2 (180390), are detectable in quiescent cells. In cycling cells, RRM1 mRNA and protein are present throughout the cell cycle (summary by Parker et al., 1994).
Byrne and Smith (1993) found that the RRM1 gene, which is located at 11p15.5, is not imprinted in Wilms tumor or in hepatoblastoma. They demonstrated transcription of both alleles in 6 Wilms tumors, 1 hepatoblastoma, and samples from adjacent kidney and liver from individuals who were constitutionally heterozygous for a TaqI polymorphism.
Because the RRM1 gene is located in a region of loss of heterozygosity (LOH) in lung tumors, Pitterle et al. (1999) screened all 19 RRM1 exons in 12 pairs of normal and tumor DNA samples and identified no mutations.
In 5 patients from 3 families (families 1, 2, and 4) with autosomal recessive progressive external ophthalmoplegia-6 (PEOB6; 620647), Shintaku et al. (2022) identified homozygous mutations in the RRM1 gene (R381H, 180410.0001 and R381C, 180410.0002). The mutations were identified by whole-exome sequencing. Ribonucleotide reductase activity was reduced in fibroblasts from patients 1a, 1b, and 2. mtDNA was reduced in proliferating fibroblasts from patients 1a, 1b, and 2 and increased in quiescent fibroblasts from patients 1b and 2. The mitochondrial dNTP pools in fibroblasts from patients 1a and 1b were generally similar to controls, whereas dGTP and dTTP pools were reduced in fibroblasts from patient 2, which Shintaku et al. (2022) hypothesized was due to abnormal nucleotide binding at the RRM1 specificity and catalytic sites.
Associations Pending Confirmation
In a patient (proband 3) with progressive external ophthalmoplegia with mitochondrial deletions, Shintaku et al. (2022) identified a heterozygous mutation (c.1281C-A, NM_001033.5; N427K) in the RRM1 gene (see 157640). The mutation affected a highly conserved residue and was not present in the gnomAD database (v2.1.1). Both unaffected brothers of the proband did not carry the mutation; the deceased mother reportedly had similar clinical manifestations, but her genotype could not be ascertained. The mutation was found by whole-exome sequencing and thus it was not certain that the patient did not have another RRM1 mutation. Proband 3 was a British white man whose symptoms began in his early forties with double vision and ptosis, which progressed to ophthalmoplegia, dysphagia, sensorineural hearing loss, and muscle atrophy. Although creatine kinase levels were normal, muscle biopsy revealed COX-deficient fibers and ragged-red fibers. Southern blot and long-range PCR of muscle DNA identified multiple mtDNA deletions.
In 2 patients (patients 1a and 1b) from a consanguineous Saudi Arabian family with autosomal recessive progressive external ophthalmoplegia-6 (PEOB6; 620647), Shintaku et al. (2022) identified homozygosity for a c.1142G-A transition (c.1142G-A, NM_001033.5) in the RRM1 gene, resulting in an arg381-to-his (R381H) substitution. The mutation, which was identified by whole-exome sequencing, segregated with disease in the family. The mutation was not present in the gnomAD database (v2.1.1). Ribonucleotide reductase activity was reduced in fibroblasts from the patients, and mtDNA was reduced in proliferating fibroblasts from the patients.
In 2 sibs (family 2) and an unrelated patient (family 4) with autosomal recessive progressive external ophthalmoplegia-6 (PEOB6; 620647), Shintaku et al. (2022) identified homozygosity for a c.1141C-T transition (c.1141C-T, NM_001033.5) in the RRM1 gene, resulting in an arg381-to-cys (R381C) substitution. The mutation was identified by whole-exome sequencing and was shown by Sanger sequencing to segregate with disease in family 2; the family of patient 4 was not tested. The mutation was present in the gnomAD database (v2.1.1) at an allele frequency of 0.0001 with no homozygotes reported. Ribonucleotide reductase activity was reduced in fibroblasts from one of the sibs in family 2, and mtDNA was reduced in proliferating fibroblasts from that sib.
Brissenden, J. E., Caras, I., Thelander, L., Francke, U. The structural gene for the M1 subunit of human ribonucleotide reductase maps to chromosome 11, band p15, in human and to chromosome 7 in mouse. Exp. Cell Res. 174: 302-308, 1988. [PubMed: 3275546] [Full Text: https://doi.org/10.1016/0014-4827(88)90165-6]
Byrne, J. A., Smith, P. J. The 11p15.5 ribonucleotide reductase M1 subunit locus is not imprinted in Wilms' tumour and hepatoblastoma. Hum. Genet. 91: 275-277, 1993. [PubMed: 8386696] [Full Text: https://doi.org/10.1007/BF00218271]
Byrne, J., Smith, P. Human polymorphic probe pE1.8 detects SacI polymorphism in the ribonucleotide reductase M1 subunit gene. Hum. Genet. 87: 376 only, 1991. [PubMed: 1677928] [Full Text: https://doi.org/10.1007/BF00200924]
Engstrom, Y., Francke, U. Assignment of the structural gene for subunit M1 of human ribonucleotide reductase to the short arm of chromosome 11. Exp. Cell Res. 158: 477-483, 1985. [PubMed: 3891388] [Full Text: https://doi.org/10.1016/0014-4827(85)90470-7]
Parker, N. J., Begley, C. G., Fox, R. M. Human R1 subunit of ribonucleotide reductase (RRM1): 5-prime flanking region of the gene. Genomics 19: 91-96, 1994. [PubMed: 8188248] [Full Text: https://doi.org/10.1006/geno.1994.1017]
Parker, N. J., Begley, C. G., Fox, R. M. Human gene for the large subunit of ribonucleotide reductase (RRM1): functional analysis of the promoter. Genomics 27: 280-285, 1995. [PubMed: 7557993] [Full Text: https://doi.org/10.1006/geno.1995.1043]
Pavloff, N., Rivard, D., Masson, S., Shen, S.-H., Mes-Masson, A.-M. Sequence analysis of the large and small subunits of human ribonucleotide reductase. DNA Seq. 2: 227-234, 1992. [PubMed: 1627826] [Full Text: https://doi.org/10.3109/10425179209020807]
Pitterle, D. M., Kim, Y.-C., Jolicoeur, E. M. C., Cao, Y., O'Briant, K. C., Bepler, G. Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1). Mammalian Genome 10: 916-922, 1999. [PubMed: 10441745] [Full Text: https://doi.org/10.1007/s003359901114]
Shintaku, J., Pernice, W. M., Eyaid, W., Gc, J. B., Brown, Z. P., Juanola-Falgarona, M., Torres-Torronteras, J., Sommerville, E. W., Hellebrekers, D. M., Blakely, E. L., Donaldson, A., van de Laar, I., and 12 others. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis. J. Clin. Invest. 132: e145660, 2022. [PubMed: 35617047] [Full Text: https://doi.org/10.1172/JCI145660]