Alternative titles; symbols
HGNC Approved Gene Symbol: MTRR
SNOMEDCT: 1296847007;
Cytogenetic location: 5p15.31 Genomic coordinates (GRCh38) : 5:7,850,859-7,901,113 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p15.31 | {Neural tube defects, folate-sensitive, susceptibility to} | 601634 | Autosomal recessive | 3 |
| Homocystinuria-megaloblastic anemia, cbl E type | 236270 | Autosomal recessive | 3 |
The MTRR gene encodes methionine synthase reductase (EC 2.1.1.135). Methionine is an essential amino acid in mammals. It is required for protein synthesis and is a central player in 1-carbon metabolism. In its activated form, S-adenosylmethionine (SAM), it is the methyl donor in hundreds of biologic transmethylation reactions and the donor of propylamine in polyamine synthesis. The eventual product of the demethylation of methionine is homocysteine, and its remethylation is catalyzed by a cobalamin-dependent enzyme, methionine synthase (MTR; 156570). Over time, the cob(I)alamin cofactor of methionine synthase becomes oxidized to cob(II)alamin, rendering the MTR enzyme inactive. Regeneration of functional enzyme requires reductive methylation via a reaction catalyzed by MTRR in which SAM is used as a methyl donor (Leclerc et al., 1998).
Using consensus sequences from bacteria to predict binding sites for FMN, FAD, and NADPH, Leclerc et al. (1998) cloned a cDNA corresponding to the 'methionine synthase reductase' reducing system required for maintenance of methionine synthase in a functional state. Northern blot analysis revealed that the gene, symbolized MTRR, is expressed as a predominant mRNA of 3.6 kb. The deduced protein, a novel member of the FNR family of electron transferases, contains 698 amino acids with a predicted molecular mass of 77.7 kD. The authenticity of the cDNA sequence was confirmed by identification of mutations in cblE patients, including a 4-bp frameshift in 2 affected sibs and a 3-bp deletion in a third patient.
Using purified recombinant human proteins, Yamada et al. (2006) found that MSR maintained MTR activity at a 1:1 stoichiometric ratio. In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced due to stabilization of apoMS in the presence of MSR. MSR was also able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, which stimulated conversion of apoMS and aquacobalamin to holoMS. Yamada et al. (2006) concluded that MSR serves as a chaperone for MS and as an aquacobalamin reductase, rather than acting solely in reductive activation of MS.
Leclerc et al. (1998) mapped the MTRR gene to chromosome 5p15.3-p15.2 by a combination of somatic cell hybrid analysis and fluorescence in situ hybridization.
In 2 sibs with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (HMAE; 236270), originally reported by Schuh et al. (1984) and Rosenblatt et al. (1985), Leclerc et al. (1998) identified a heterozygous truncating mutation in the MTRR gene (602568.0001). A second mutation was not found. Another unrelated patient carried a different truncation mutation (602568.0002); a second mutation was not found. The disorder, which is a defect of cobalamin metabolism, was characterized by megaloblastic anemia, developmental delay, hyperhomocysteinemia, and hypomethioninemia.
By RT-PCR, heteroduplex, single-strand conformation polymorphism (SSCP), and DNA sequence analyses Wilson et al. (1999) identified 11 mutations in 8 patients from 7 families belonging to the cblE complementation group of patients with defects in methionine synthase reductase. The mutations included splicing defects that led to large insertions or deletions, as well as a number of smaller deletions and point mutations. Apart from an intronic substitution found in 2 unrelated patients, the mutations appeared singular among individuals. Of the 11, 3 were nonsense mutations, allowing for the identification of 2 patients for whom little if any MSR protein should be produced. The remaining 8 involved point mutations or in-frame disruptions of the coding sequence and were distributed throughout the coding region. The data demonstrated a unique requirement for MSR in reductive activation of methionine synthase.
Zavadakova et al. (2002) identified 3 novel mutations (602568.0004-602568.0006) in the MTRR gene causing cblE type homocystinuria.
Using gene-trap techniques, Padmanabhan et al. (2013) created a hypomorphic mutation in the mouse Mtrr gene that resulted in increased plasma homocysteine, an indicator of folate deficiency. The Mtrr mutation resulted in intrauterine growth restriction, developmental delay, and congenital malformation, including neural tube, heart, and placental defects. However, these effects did not correlate with the embryonic Mtrr genotypes, but rather with the Mtrr genotypes of the maternal grandparents. Mtrr deficiency in either maternal grandparent was sufficient to cause defects in grandprogeny at embryonic day 10.5. Mtrr deficiency caused tissue-specific global DNA hypomethylation. The authors observed widespread epigenetic instability associated with altered gene expression in wildtype grandprogeny of Mtrr-deficient maternal grandparents. Embryo transfer experiments showed that Mtrr deficiency led to 2 distinct, separable phenotypes: adverse effects on the uterine environment of their wildtype daughters, leading to growth defects in wildtype grandprogeny, and the appearance of congenital malformations, independent of maternal environment, that persisted for 5 generations. Padmanabhan et al. (2013) proposed that hypomorphic mutations in the MTRR gene associated with reduced expression may lead to congenital abnormalities, even with normal dietary folate. Moreover, the transgenerational effect of MTRR deficiency may only be overcome by folate fortification for more than 1 generation.
In 2 sibs with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (HMAE; 236270), originally reported by Schuh et al. (1984) and Rosenblatt et al. (1985), Leclerc et al. (1998) used RT-PCR-dependent heteroduplex analysis and sequencing to identify a heterozygous 1675del4 deletion in the MTRR gene, resulting in a frameshift and nearby stop codon. A second mutation was not found.
In a patient with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270), Leclerc et al. (1998) identified a 1726delTTG mutation that resulted in the loss of a highly conserved leucine at position 576 of the amino acid sequence of the protein product. This mutation was present in heterozygous state. On direct sequencing of the PCR products, only a very faint background contributed by the allele that showed no abnormality on heteroduplex analysis was observed, suggesting that the other, unidentified mutation in this patient was associated with a very low level of steady-state mRNA. This patient had originally been reported by Tauro et al. (1976) as having dihydrofolate reductase deficiency (613839).
The cloning of the cDNA for MTRR (Leclerc et al., 1998) led to the identification of a 66A-G polymorphism, resulting in an ile22-to-met (I22M) substitution, that was shown by Wilson et al. (1999) to be associated with increased risk for the neural tube defect spina bifida (see 601634). Serum deficiency of vitamin B12 increased the effect.
Hobbs et al. (2000) evaluated the frequencies of the MTHFR 677C-T (607093.0003) and MTRR 66A-G polymorphisms in DNA samples from 157 mothers of children with Down syndrome (190685) and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results were consistent with the preliminary observations of James et al. (1999) that the MTHFR 677C-T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio (OR) of 1.91 (95% CI, 1.19-3.05). In addition, the homozygous MTRR 66A-G polymorphism was independently associated with a 2.57-fold increase in estimated risk (95% CI, 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an OR of 4.08 (95% CI, 1.94-8.56). The 2 polymorphisms appeared to act without a multiplicative interaction. The association between folate deficiency and DNA hypomethylation lent support to the possibility that the increased frequency of the MTHFR and MTTR polymorphisms observed in this study may be associated with chromosomal nondisjunction and Down syndrome.
Doolin et al. (2002) studied the potential involvement of both the maternal and embryonic genotypes in determining risk of spina bifida. Analysis of data on this polymorphism and the A2756G polymorphism of the methionine synthase gene (156570.0008) provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants the risk of having a child with spina bifida appeared to increase with the number of high-risk alleles in the maternal genotype.
Bosco et al. (2003) studied the influence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C-T and 1298A-C, 607093.0004), methionine synthase (MTR 2756A-G), and methionine synthase reductase (MTRR 66A-G) on the risk of being a Down syndrome (190685) case or of having a child with Down syndrome (case mother). Plasma homocysteine and other factors were likewise studied. They found that after adjustment for age, total homocysteine and MTR 2756 AG/GG genotype were significant risk factors for having a Down syndrome child, with odds ratio (OR) of 6.7 and 3.5, respectively. The MTR 2756 AG/GG genotype increased significantly the risk of being a Down syndrome case, with an OR of 3.8. Double heterozygosity for MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a Down syndrome child, with an OR estimated at 5.0, after adjustment for total homocysteine level.
O'Leary et al. (2005) found no association between the 66A-G polymorphism and neural tube defects in an Irish population comprising 470 patients and 447 mothers of cases. A dominant paternal effect was observed (OR of 1.46).
In a 20-year-old woman with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270) who presented with megaloblastic anemia at 10 weeks of age, Zavadakova et al. (2002) identified compound heterozygosity for a G-to-A transition at nucleotide 1459 of the MTRR gene on one allele, leading to a glycine-to-arginine substitution at codon 487 (G487R), and a 2-bp insertion on the other allele (see 602568.0005). The patient was treated with folates and vitamin B12, and subsequent attempts to cease administration of folates led to recurrence of megaloblastic anemia. Biochemical features included severe hyperhomocysteinemia and hypomethioninemia and, in fibroblasts, defective formation of methionine from formate, and no complementation with cblE cells.
The second mutation of the compound heterozygous patient reported by Zavadakova et al. (2002) (see 602568.0004) was a 2-bp insertion after nucleotide 1623 of the MTRR gene (1623-1624insTA).
Zavadakova et al. (2002) reported an 8-year-old girl with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270) in whom megaloblastic anemia was detected at 11 weeks of age. She had nystagmus, hyperkinesis, and developmental delay that resolved with age. Severe hyperhomocysteinemia with normal methionine levels was found and enzymatic and complementation studies confirmed the cobalamin E defect. The patient was homozygous for a 140-bp insertion (903-904ins140). The insertion was caused by a T-to-C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer. Both the patients' parents originated from the same geographic region, and the family history pointed to possible consanguinity.
Wilson et al. (1999) identified this mutation in 2 patients.
In a group of 9 patients of European origin with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type (236270), Zavadakova et al. (2005) found a 1361C-T transition in the MTRR gene causing a ser454-to-leu (S454L) substitution in 5 independent alleles, either in a homozygous state (2 patients) or a heterozygous state (1 patient). The S454L mutation had been found only in patients of Spanish or Portuguese ancestry, supporting the idea that this is an Iberian mutation. The 2 homozygous patients were mildly affected without severe neurologic involvement.
Bosco, P., Gueant-Rodriguez, R. M., Anello, G., Barone, C., Namour, F., Caraci, F., Romano, A., Romano, C., Gueant, J. L. Methionine synthase (MTR) 2756 (A-G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are 3 risk factors for having a child with Down syndrome. Am. J. Med. Genet. 121A: 219-224, 2003. [PubMed: 12923861] [Full Text: https://doi.org/10.1002/ajmg.a.20234]
Doolin, M.-T., Barbaux, S., McDonnell, M., Hoess, K., Whitehead, A. S., Mitchell, L. E. Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am. J. Hum. Genet. 71: 1222-1226, 2002. [PubMed: 12375236] [Full Text: https://doi.org/10.1086/344209]
Hobbs, C. A., Sherman, S. L., Yi, P., Hopkins, S. E., Torfs, C. P., Hine, R. J., Pogribna, M., Rozen, R., James, S. J. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am. J. Hum. Genet. 67: 623-630, 2000. [PubMed: 10930360] [Full Text: https://doi.org/10.1086/303055]
James, S. J., Pogribna, M., Pogribny, I. P., Melnyk, S., Hine, R. J., Gibson, J. B., Yi, P., Tafoya, D. L., Swenson, D. H., Wilson, V. L., Gaylor, D. W. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am. J. Clin. Nutr. 70: 495-501, 1999. [PubMed: 10500018] [Full Text: https://doi.org/10.1093/ajcn/70.4.495]
Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc. Nat. Acad. Sci. 95: 3059-3064, 1998. [PubMed: 9501215] [Full Text: https://doi.org/10.1073/pnas.95.6.3059]
O'Leary, V. B., Mills, J. L., Pangilinan, F., Kirke, P. N., Cox, C., Conley, M., Weiler, A., Peng, K., Shane, B., Scott, J. M., Parle-McDermott, A., Molloy, A. M., Brody, L. C. Members of the Birth Defects Research Group: Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Molec. Genet. Metab. 85: 220-227, 2005. [PubMed: 15979034] [Full Text: https://doi.org/10.1016/j.ymgme.2005.02.003]
Padmanabhan, N., Jia, D., Geary-Joo, C., Wu, X., Ferguson-Smith, A. C., Fung, E., Bieda, M. C., Snyder, F. F., Gravel, R. A., Cross, J. C., Watson, E. D. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155: 81-93, 2013. [PubMed: 24074862] [Full Text: https://doi.org/10.1016/j.cell.2013.09.002]
Rosenblatt, D. S., Cooper, B. A., Schmutz, S. M., Zaleski, W. A., Casey, R. E. Prenatal vitamin B-12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease). Lancet 325: 1127-1129, 1985. Note: Originally Volume I. [PubMed: 2860337] [Full Text: https://doi.org/10.1016/s0140-6736(85)92433-x]
Schuh, S., Rosenblatt, D. S., Cooper, B. A., Schroeder, M.-L., Bishop, A. J., Seargeant, L. E., Haworth, J. C. Homocystinuria and megaloblastic anemia responsive to vitamin B-12 therapy. New Eng. J. Med. 310: 686-690, 1984. [PubMed: 6700644] [Full Text: https://doi.org/10.1056/NEJM198403153101104]
Tauro, G. P., Danks, D. M., Rowe, P. B., Van der Weyden, M. B., Schwarz, M. A., Collins, V. L., Neal, B. W. Dihydrofolate reductase deficiency causing megaloblastic anemia in two families. New Eng. J. Med. 294: 466-470, 1976. [PubMed: 1060915] [Full Text: https://doi.org/10.1056/NEJM197602262940903]
Wilson, A., Leclerc, D., Rosenblatt, D. S., Gravel, R. A. Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism. Hum. Molec. Genet. 8: 2009-2016, 1999. [PubMed: 10484769] [Full Text: https://doi.org/10.1093/hmg/8.11.2009]
Wilson, A., Platt, R., Wu, Q., Leclerc, D., Christensen, B., Yang, H., Gravel, R. A., Rozen, R. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Molec. Genet. Metab. 67: 317-323, 1999. [PubMed: 10444342] [Full Text: https://doi.org/10.1006/mgme.1999.2879]
Yamada, K., Gravel, R. A., Toraya, T., Matthews, R. G. Human methionine synthase reductase is a molecular chaperone for human methionine synthase. Proc. Nat. Acad. Sci. 103: 9476-9481, 2006. [PubMed: 16769880] [Full Text: https://doi.org/10.1073/pnas.0603694103]
Zavadakova, P., Fowler, B., Suormala, T., Novotna, Z., Mueller, P., Hennermann, J. B., Zeman, J., Vilaseca, M. A., Vilarinho, L., Gutsche, S., Wilichowski, E., Horneff, G., Kozich, V. cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. Hum. Mutat. 25: 239-247, 2005. Note: Erratum: Hum. Mutat. 26: 590 only, 2005. [PubMed: 15714522] [Full Text: https://doi.org/10.1002/humu.20131]
Zavadakova, P., Fowler, B., Zeman, J., Suormala, T., Pristoupilova, K., Kozich, V. CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in 2 families. J. Inherit. Metab. Dis. 25: 461-476, 2002. Note: Erratum: J. Inherit. Metab. Dis. 26: 95 only, 2003. [PubMed: 12555939] [Full Text: https://doi.org/10.1023/a:1021299117308]