Alternative titles; symbols
HGNC Approved Gene Symbol: RRM2B
SNOMEDCT: 765100000;
Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38): 8:102,204,501-102,238,961 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.3 | Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) | 612075 | Autosomal recessive | 3 |
| Mitochondrial DNA depletion syndrome 8B (MNGIE type) | 612075 | Autosomal recessive | 3 | |
| Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 | 613077 | Autosomal dominant | 3 | |
| Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction | 268315 | Autosomal recessive | 3 |
The RRM2B gene encodes the small subunit of p53 (191170)-inducible ribonucleotide reductase, a heterotetrameric enzyme responsible for de novo conversion of ribonucleoside diphosphates into the corresponding deoxyribonucleoside diphosphates that are essential for DNA synthesis (Bourdon et al., 2007).
The p53 gene is frequently inactivated in human cancers. By using differential display to examine mRNAs in a human colon cancer cell line carrying a highly regulated wildtype p53 expression system, Tanaka et al. (2000) detected a 5.5-kb transcript that was inducible by wildtype p53 but not mutant p53. Using the differential display fragment representing this transcript as a probe to screen a skeletal muscle cDNA library, they isolated a cDNA sequence that incorporated an open reading frame of 351 amino acids with 80% identity to the small subunit of human ribonucleotide reductase (R2; 180390). Comparison of this sequence, which they called p53R2 for 'p53-inducible ribonucleotide reductase small subunit 2 homolog,' with those of yeast RNR2 and RNR4 revealed 60% and 40% identity, respectively. Tanaka et al. (2000) considered p53R2 to be a human counterpart of yeast RNR2. The protein has a ribonucleotide reductase small subunit signature and 2 putative nuclear localization signal sequences.
Tanaka et al. (2000) found that the p53R2 gene consists of 9 exons and spans a 30-kb genomic region. Electromobility shift assays identified a 20-nucleotide region in intron 1 as the p53 binding site.
Tanaka et al. (2000) mapped the p53R2 gene to chromosome 8q23.1 by fluorescence in situ hybridization.
Stumpf (2022) mapped the RRM2B gene to chromosome 8q22.3 based on an alignment of the RRM2B sequence (GenBank BC117496) with the genomic sequence (GRCh38).
Tanaka et al. (2000) found that expression of p53R2, but not R2, was induced by ultraviolet and gamma-irradiation and adriamycin treatment in a wildtype p53-dependent manner. Induction of p53R2 in p53-deficient cells caused G2/M arrest and protected cells from death in response to adriamycin. Inhibition of endogenous p53R2 expression in cells that had an intact p53-dependent DNA damage checkpoint reduced ribonucleotide reductase activity, DNA repair, and cell survival after exposure to various genotoxins. Tanaka et al. (2000) demonstrated nuclear accumulation of p53R2 protein in response to genotoxic stress induced by gamma-irradiation. Tanaka et al. (2000) concluded that p53R2 encodes a ribonucleotide reductase that is directly involved in the p53 checkpoint for repair of damaged DNA. The discovery of p53R2 clarified a relationship between a ribonucleotide reductase activity involved in repair of damaged DNA and tumor suppression by p53. Tanaka et al. (2000) proposed that inactivation of p53 directly interferes with the transcription of p53R2 in response to DNA damage, with the result that ribonucleotide reductase activity is insufficient for normal DNA repair. Faulty regulation of p53R2 might also enhance misincorporation of deoxyribonucleotide triphosphates (dNTPs) and dysregulation of DNA repair machinery and thereby increase the frequency of mutations. Tanaka et al. (2000) suggested that the genomic instability often seen in tumors lacking wildtype p53 may reflect dysfunction of ribonucleotide reductase due to the failure of p53R2 induction.
Mitochondrial DNA Depletion Syndrome 8A (Encephalomyopathic Type with Renal Tubulopathy)
In 7 patients from 4 families with severe autosomal recessive mitochondrial DNA (mtDNA) depletion syndrome-8A (MTDPS8A; 612075), associated with renal tubulopathy, Bourdon et al. (2007) identified homozygous or compound heterozygous mutations in the RRM2B gene (see, e.g., 604712.0001-604712.0005). All patients had 1 to 2% residual mtDNA in skeletal muscle and died in the first months of life with severe lactic acidosis. Respiratory chain complex activities were severely decreased in muscle from these patients. The findings indicated that RRM2B plays a crucial role in dNTP supply, especially for the synthesis of mtDNA.
In a male infant, born to consanguineous Latino parents, with MTDPS8A, Penque et al. (2019) identified a homozygous missense mutation in the RRM2B gene (N221S; 604712.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Molecular modeling suggested that the mutation disrupts a conserved alpha helix region of the protein by altering intramolecular interactions.
Mitochondrial DNA Depletion Syndrome 8B (MNGIE Type)
Shaibani et al. (2009) identified compound heterozygosity for 2 mutations in the RRM2B gene (R110H, 604712.0008; R121H, 604712.0009) in a 42-year-old woman with mtDNA depletion syndrome-8B, manifest as a neurogastrointestinal encephalopathy (see 612075). The authors stated that this was the oldest reported patient with RRM2B mutations and that her clinical course was different from that reported previously in patients with MNGIE.
Autosomal Dominant Progressive External Ophthalmoplegia 5
By linkage analysis followed by candidate gene sequencing in a large North American family with mild autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Tyynismaa et al. (2009) identified a heterozygous mutation in the RRM2B gene (R327X; 604712.0006) that segregated with the disorder. Affected members of an unrelated Hungarian family carried the same mutation, but there was no evidence of a common origin.
By direct sequencing of the RRM2B gene in 75 unrelated probands with PEO in whom mutations in other known PEO-related genes had been excluded, Fratter et al. (2011) identified 3 different heterozygous truncating mutations in the RRM2B gene (see, e.g., 604712.0010 and 604712.0011) in 7 (9.3%) patients. The findings suggested that truncating RRM2B mutations are rather frequent in familial PEO with mtDNA deletions. Three additional patients were found to carry 3 different heterozygous missense variants, but the pathogenicity of the variants was considered provisional in the absence of further supporting evidence.
Rod-Cone Dystrophy, Sensorineural Deafness, and Fanconi-Type Renal Dysfunction
In 6 patients from 5 Afrikaner families with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD; 268315), Roberts et al. (2020) identified homozygosity for a missense mutation in the RRM2B gene (E262D; 604712.0016) that segregated with disease in each family and was not found in Afrikaner controls or in public variant databases. Haplotype analysis suggested a probable founder effect in the Afrikaner population. Evaluation of a patient muscle biopsy showed no evidence of mtDNA deletions or depletion, but microscopy was consistent with a mild mitochondrial abnormality.
To determine whether ribonucleotide reductase is involved in DNA repair by supplying deoxyribonucleotides (dNTPs) for resting cells in vivo, Kimura et al. (2003) generated a strain of mice lacking Rrm2b. These mice developed normally until they were weaned but from then on had growth retardation and early mortality. Pathologic examination indicated that multiple organs had failed, and all Rrm2b-null mice died from severe renal failure by the age of 14 weeks. TUNEL staining showed a greater number of apoptotic cells in kidneys of 8-week-old null mice relative to wildtype. p53 (191170) was activated in kidney tissues of the null mice, leading to transcriptional induction of p53 target genes. Embryonic fibroblasts from null mice became immortal much earlier than wildtype embryonic fibroblasts. dNTP pools were severely attenuated in embryonic fibroblasts from null mice under oxidative stress. Rrm2b deficiency caused higher rates of spontaneous mutation in the kidneys of null mice. The results suggested that p53R2 has a pivotal role in maintaining dNTP levels for repair of DNA in resting cells. Impairment of this pathway may enhance spontaneous mutation frequency and activate p53-dependent apoptotic pathways in vivo, causing severe renal failure, growth retardation, and early mortality.
Bourdon et al. (2007) found that 12-week-old Rrm2b-null mice had markedly decreased mtDNA content in kidney (5.57% of controls), muscle (5.24%), and liver (21%).
In 3 sibs, born of consanguineous Moroccan parents, with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), manifest as encephalomyopathy and renal tubulopathy, Bourdon et al. (2007) identified a homozygous 850C-T transition in the RRM2B gene, resulting in a gln284-to-ter (Q284X) substitution. The substitution resulted in the deletion of the last 68 C-terminal residues of the protein, including part of the an alpha-helix as well as the heptapeptide involved in the binding to R1. The sibs had hypotonia and lactic acidosis and died within the first months of life. Severe mtDNA depletion (less than 1% of controls) was found in muscle of 1 the sibs.
In 2 French infants with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), manifest as encephalomyopathy with renal tubulopathy, Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: an A-to-G transition in intron 3 and E194K (604712.0003). The sibs had lactic acidemia, hypotonia, tubulopathy, and seizures. Only 2% of normal mtDNA levels was detected in the muscle of 1 of the sibs. Both died at 2 months of age.
In 2 French infants with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), manifest as encephalomyopathy with renal tubulopathy, Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 580G-A transition, resulting in a glu194-to-lys (E194K) substitution, and a splice site mutation (604712.0002). Residue 194 is involved in iron binding.
In a French infant with severe mitochondrial DNA depletion with renal tubulopathy (612075), Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 3-bp deletion (253delGAG), resulting in an in-frame deletion of glu85, and C236F (604712.0005). The patient had neonatal hypotonia and increased plasma and CSF lactate; she died at age 3 months. Muscle histology showed ragged-red fibers, and mtDNA content was about 1% of normal. The deletion of glu85 was predicted to disrupt the local subdomain structure and the dimerization interface between R1 and R2.
In a French infant with severe mitochondrial DNA depletion with renal tubulopathy (612075), Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 707G-T transversion, resulting in a cys236-to-phe (C236F) substitution, and a 3-bp deletion (604712.0004).
In affected members of 2 unrelated families with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Tyynismaa et al. (2009) identified a heterozygous 979C-T transition in the last exon of the RRM2B gene, resulting in an arg327-to-ter (R327X) substitution. The substitution was predicted to result in a protein lacking the last 25 amino acids. One family was North American of European origin, and the second was Hungarian. The mutation was not observed in 380 control European chromosomes, and there was no evidence of a founder effect. The phenotype was characterized by late-onset of mild ophthalmoplegia and mild muscle weakness. Skeletal muscle biopsies showed mtDNA deletions, but normal mtDNA copy numbers. RNA studies showed that the R328X mRNA escaped nonsense-mediated decay, and that the mutant protein was expressed and stable. The findings suggested that the mutant RRM2B protein can compete with wildtype in binding to ribonucleotide reductase, causing a dominant-negative or gain-of-function effect.
In 2 Sudanese brothers, born of consanguineous parents, with encephalomyopathic mitochondrial DNA depletion syndrome (MTDPS8A; 612075), Kollberg et al. (2009) identified a homozygous 686G-T transversion in exon 7 of the RRM2B gene, resulting in a gly229-to-val (G229V) substitution in the diferric iron center of the protein. Each unaffected parent was heterozygous for the mutation. The phenotype was severe, with hypotonia, seizures, poor visual contact, and lactic acidosis, and both patients died by 5 months of age. One boy developed a proximal renal tubulopathy. Southern blot analysis of patient cells showed severe mtDNA depletion, about 1 to 4% of normal controls.
In a 42-year-old woman with mitochondrial DNA depletion syndrome-8B, manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE; see 612075), Shaibani et al. (2009) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 329G-A transition resulting in an arg110-to-his (R110H) substitution, and a 362G-A transition resulting in an arg121-to-his (R121H; 604712.0009) substitution. Both mutations occurred in highly conserved residues. The patient developed recurrent nausea, vomiting, and weight loss at age 30 years. At age 37, she developed restriction of eye movements, ptosis, dysarthria, unsteady gait, muscle weakness, and areflexia consistent with a peripheral neuropathy. Skeletal muscle showed mtDNA depletion (12% of controls). Shaibani et al. (2009) noted that this was the oldest reported patient with RRM2B mutations and that her clinical course was different from that reported previously in patients with MNGIE. The findings also broadened the phenotype associated with RRM2B mutations to include an MNGIE-like picture.
For discussion of the arg121-to-his (R121H) mutation in the RRM2B gene that was found in compound heterozygous state in a patient with mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE; see 612075) by Shaibani et al. (2009), see 604712.0008.
In 3 unrelated patients with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Fratter et al. (2011) identified a heterozygous 1-bp deletion (950delT) in the RRM2B gene, resulting in a frameshift and premature termination at leu317. The patients had onset at ages 30, 53, and 46 years, and all had a family history of the disorder. All had PEO and ptosis, but additional variable features in 2 patients included fatigue, ataxia, proximal myopathy, dysphagia, and glaucoma. Skeletal muscle biopsies of the probands showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. The mutation was not found in 352 control alleles.
In 3 unrelated patients with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Fratter et al. (2011) identified a heterozygous 1-bp duplication (965dupA) in the RRM2B gene, resulting in a frameshift and premature termination. The patients had onset at ages 30, 54, and 26 years, and all had a family history of the disorder. All had PEO and fatigue, but additional features were variable and included diabetes, gastrointestinal symptoms, dysphagia, dysphonia, and proximal myopathy. Skeletal muscle biopsies of the probands showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. The mutation was not found in 352 control alleles.
This variant is classified as a variant of unknown significance because its contribution to progressive external ophthalmoplegia (PEO) has not been confirmed.
In a 14-year-old patient with early-onset PEO at age 4 and hearing loss, Fratter et al. (2011) identified compound heterozygous changes in the RRM2B gene: a 606T-A transversion resulting in a phe202-to-leu (F202L) substitution, and an 817G-A transition resulting in a gly273-to-ser (G273S; 604712.0013) substitution. Functional studies of the variants were not performed. Skeletal muscle biopsy showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. Neither variant was found in 352 control alleles, and both occurred in conserved residues. There was no family history of a similar disorder, but information on the parents was not provided. The findings suggested recessive inheritance of the disorder.
For discussion of the gly273-to-ser (G273S) mutation in the RRM2B gene that was found in compound heterozygous state in a patient with early-onset progressive external ophthalmoplegia (PEO) and hearing loss by Fratter et al. (2011) and classified as a variant of unknown significance, see 604712.0012.
This variant is classified as a variant of unknown significance because its contribution to progressive external ophthalmoplegia (PEO) has not been confirmed.
In a 43-year-old Japanese man, born of consanguineous parents, with adult-onset PEO, Takata et al. (2011) identified a homozygous 341G-A transition in the RRM2B gene, resulting in a pro33-to-ser (P33S) substitution in a highly conserved residue in the N terminus. The variant was found by whole-exome sequencing in combination with runs of homozygosity analysis. Each unaffected parent was heterozygous for the mutation, which was found in 1 of 718 control chromosomes of Japanese origin. Functional studies of the variant were not performed. The patient presented with hearing loss at age 16 years, and later developed ptosis, ophthalmoplegia, and muscle weakness. He also had pigmentary degeneration of the retina and gonadal atrophy. Other features included depressed mood, anxiety, and hypochondriacal complaints. Muscle biopsy showed marked variation of fiber size, ragged-red fibers, COX-negative fibers, and multiple mtDNA deletions. There was no family history of a similar disorder. Mutations in other candidate genes were excluded. Takata et al. (2011) suggested that this was the first case of recessive inheritance of PEO due to RRM2B mutations.
In a male infant, born to consanguineous Latino parents, with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), Penque et al. (2019) identified homozygosity for a c.662A-G transition (c.662A-G, NM_015713) in the RRM2B gene, resulting in an asn221-to-ser (N221S) substitution at a conserved residue in a highly conserved alpha helix region close to 2 known iron-binding sites. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present in 1 of 250,000 alleles in the gnomAD database. Molecular modeling suggested that the mutation disrupts the conserved alpha helix region by altering intramolecular interactions.
In 6 patients from 5 unrelated Afrikaner families with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD; 268315), including 2 sisters who were originally reported by Beighton et al. (1993) as patients 1 and 2, Roberts et al. (2020) identified homozygosity for a c.786G-T transversion (c.786G-T, NM_015713.4) in exon 7 of the RRM2B gene, resulting in a glu262-to-asp (E262D) substitution at a highly conserved residue within helix G of the p53R2 monomer. The mutation segregated with disease in the families and was not found in 34 healthy Afrikaner controls or in the 1000 Genomes Project, ExAC, or gnomAD v2.11 databases. Haplotype analysis suggested a probable founder effect in the Afrikaner population.
Beighton, P., Bartmann, L., Bingham, G., Sellars, S. Rod-cone dystrophy, sensorineural deafness, and renal dysfunction: an autosomal recessive syndrome. Am. J. Med. Genet. 47: 832-836, 1993. [PubMed: 8279480] [Full Text: https://doi.org/10.1002/ajmg.1320470607]
Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter) Nature Genet. 39: 776-780, 2007. [PubMed: 17486094] [Full Text: https://doi.org/10.1038/ng2040]
Fratter, C., Raman, P., Alston, C. L., Blakely, E. L., Craig, K., Smith, C., Evans, J., Seller, A., Czermin, B., Hanna, M. G., Poulton, J., Brierley, C., Staunton, T. G., Turnpenny, P. D., Schaefer, A. M., Chinnery, P. F., Horvath, R., Turnbull, D. M., Gorman, G. S., Taylor, R. W. RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions. Neurology 76: 2032-2034, 2011. [PubMed: 21646632] [Full Text: https://doi.org/10.1212/WNL.0b013e31821e558b]
Kimura, T., Takeda, S., Sagiya, Y., Gotoh, M., Nakamura, Y., Arakawa, H. Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools. Nature Genet. 34: 440-445, 2003. [PubMed: 12858174] [Full Text: https://doi.org/10.1038/ng1212]
Kollberg, G., Darin, N., Benan, K., Moslemi, A.-R., Lindal, S., Tulinius, M., Oldfors, A., Holme, E. A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromusc. Disord. 19: 147-150, 2009. [PubMed: 19138848] [Full Text: https://doi.org/10.1016/j.nmd.2008.11.014]
Penque, B. A., Su, L., Wang, J., Ji, W., Bale, A., Luh, F., Fulbright, R. K., Fulbright, R. K., Sarmast, U., Sega, A. G., Konstantino, M., Spencer-Manzon, M., Pierce, R., Yen, Y., Lakhani, S. A. A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death. Europ. J. Med. Genet. 62: 103574, 2019. Note: Electronic Article. [PubMed: 30439532] [Full Text: https://doi.org/10.1016/j.ejmg.2018.11.008]
Roberts, L., Julius, S., Dawlat, S., Yildiz, S., Rebello, G., Meldau, S., Pillay, K., Esterhuizen, A., Vorster, A., Benefeld, G., da Rocha, J., Beighton, P., Sellars, S. L., Thandrayen, K., Pettifor, J. M., Ramesar, R. S. Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B. Hum. Mutat. 41: 1871-1876, 2020. [PubMed: 32827185] [Full Text: https://doi.org/10.1002/humu.24094]
Shaibani, A., Shchelochkov, O. A., Zhang, S., Katsonis, P., Lichtarge, O., Wong, L.-J., Shinawi, M. Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch. Neurol. 66: 1028-1032, 2009. [PubMed: 19667227] [Full Text: https://doi.org/10.1001/archneurol.2009.139]
Stumpf, A. M. Personal Communication. Baltimore, Md. 03/01/2022.
Takata, A., Kato, M., Nakamura, M., Yoshikawa, T., Kanba, S., Sano, A., Kato, T. Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome Biol. 12: R92, 2011. Note: Electronic Article. [PubMed: 21951382] [Full Text: https://doi.org/10.1186/gb-2011-12-9-r92]
Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404: 42-49, 2000. [PubMed: 10716435] [Full Text: https://doi.org/10.1038/35003506]
Tyynismaa, H., Ylikallio, E., Patel, M., Molnar, M. J., Haller, R. G., Suomalainen, A. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am. J. Hum. Genet. 85: 290-295, 2009. [PubMed: 19664747] [Full Text: https://doi.org/10.1016/j.ajhg.2009.07.009]