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MIM
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OMIM | *602568 | METHIONINE SYNTHASE REDUCTASE; MTRR

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MIM
*602568
Title
METHIONINE SYNTHASE REDUCTASE; MTRR
Alternative titles; symbols
MSR
Morbid map
{Neural tube defects, folate-sensitive, susceptibility to}, 601634 (3)MTRR
Homocystinuria-megaloblastic anemia, cbl E type, 236270 (3)MTRR
Chromosome
5
Gene map locus
5p15.3-p15.2
Gene map
236270
601634
Disorder
Homocystinuria-megaloblastic anemia, cbl E type, 236270 (3); {Neural tube defects, folate-sensitive, susceptibility to}, 601634 (3)
Method
Psh, A
Text
DESCRIPTIONThe 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).
CLONINGUsing 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.
GENE FUNCTIONUsing 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.
MAPPINGLeclerc 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.
MOLECULAR GENETICSPatients of the cblE complementation group of disorders of folate/cobalamin metabolism who are defective in reductive activation of methionine synthase exhibit 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.
Allelic variants
.0001HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblE COMPLEMENTATION TYPE MTRR, 4-BP DEL, NT1675In 2 sibs with homocystinuria-megaloblastic anemia due to defects incobalamin metabolism, cblE type (236270), Leclerc et al. (1998) usedRT-PCR-dependent heteroduplex analysis and sequencing to identify a1675del4 deletion in the MTRR gene, resulting in a frameshift and nearbystop codon.
.0002HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblE COMPLEMENTATION TYPE MTRR, 3-BP DEL, 1726TTGIn a patient with homocystinuria-megaloblastic anemia due to defects incobalamin metabolism, cblE type (236270), Leclerc et al. (1998)identified a 1726delTTG mutation that resulted in the loss of a highlyconserved leucine at position 576 of the amino acid sequence of theprotein product. This mutation was present in heterozygous state. Ondirect sequencing of the PCR products, only a very faint backgroundcontributed by the allele that showed no abnormality on heteroduplexanalysis was observed, suggesting that the other, unidentified mutationin this patient was associated with a very low level of steady-statemRNA.
.0003NEURAL TUBE DEFECTS, FOLATE-SENSITIVE, SUSCEPTIBILITY TO DOWN SYNDROME, SUSCEPTIBILITY TO, INCLUDED MTRR, ILE22METThe cloning of the cDNA for MTRR (Leclerc et al., 1998) led to theidentification of a 66A-G polymorphism, resulting in an ile22-to-met(I22M) substitution, that was shown by Wilson et al. (1999) to beassociated 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 157mothers of children with Down syndrome (190685) and 144 control mothers.Odds ratios were calculated for each genotype separately and forpotential gene-gene interactions. The results were consistent with thepreliminary observations of James et al. (1999) that the MTHFR 677C-Tpolymorphism is more prevalent among mothers of children with Downsyndrome 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 polymorphismwas independently associated with a 2.57-fold increase in estimated risk(95% CI, 1.33-4.99). The combined presence of both polymorphisms wasassociated with a greater risk of Down syndrome than was the presence ofeither alone, with an OR of 4.08 (95% CI, 1.94-8.56). The 2polymorphisms appeared to act without a multiplicative interaction. Theassociation between folate deficiency and DNA hypomethylation lentsupport to the possibility that the increased frequency of the MTHFR andMTTR polymorphisms observed in this study may be associated withchromosomal nondisjunction and Down syndrome. Doolin et al. (2002) studied the potential involvement of both thematernal and embryonic genotypes in determining risk of spina bifida.Analysis of data on this polymorphism and the A2756G polymorphism of themethionine synthase gene (156570.0008) provided evidence that bothvariants influence the risk of spina bifida via the maternal rather thanthe embryonic genotype. For both variants the risk of having a childwith spina bifida appeared to increase with the number of high-riskalleles in the maternal genotype. Bosco et al. (2003) studied the influence of polymorphisms ofmethylenetetrahydrofolate reductase (MTHFR 677C-T and 1298A-C,607093.0004), methionine synthase (MTR 2756A-G), and methionine synthasereductase (MTRR 66A-G) on the risk of being a Down syndrome (190685)case or of having a child with Down syndrome (case mother). Plasmahomocysteine and other factors were likewise studied. They found thatafter adjustment for age, total homocysteine and MTR 2756 AG/GG genotypewere significant risk factors for having a Down syndrome child, withodds ratio (OR) of 6.7 and 3.5, respectively. The MTR 2756 AG/GGgenotype 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 wasthe single combined genotype that was a significant risk factor forhaving a Down syndrome child, with an OR estimated at 5.0, afteradjustment for total homocysteine level. O'Leary et al. (2005) found no association between the 66A-Gpolymorphism and neural tube defects in an Irish population comprising470 patients and 447 mothers of cases. A dominant paternal effect wasobserved (OR of 1.46).
.0004HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblE COMPLEMENTATION TYPE MTRR, GLY487ARGIn a 20-year-old woman with homocystinuria-megaloblastic anemia due todefects in cobalamin metabolism, cblE type (236270) who presented withmegaloblastic anemia at 10 weeks of age, Zavadakova et al. (2002)identified compound heterozygosity for a G-to-A transition at nucleotide1459 of the MTRR gene on one allele, leading to a glycine-to-argininesubstitution at codon 487 (G487R), and a 2-bp insertion on the otherallele (see 602568.0005). The patient was treated with folates andvitamin B12, and subsequent attempts to cease administration of folatesled to recurrence of megaloblastic anemia. Biochemical features includedsevere hyperhomocysteinemia and hypomethioninemia and, in fibroblasts,defective formation of methionine from formate, and no complementationwith cblE cells.
.0005HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblE COMPLEMENTATION TYPE MTRR, 2-BP INS, 1623TAThe second mutation of the compound heterozygous patient reported byZavadakova et al. (2002) (see 602568.0004) was a 2-bp insertion afternucleotide 1623 of the MTRR gene (1623-1624insTA).
.0006HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblE COMPLEMENTATION TYPE MTRR, 140-BP INS, NT903Zavadakova et al. (2002) reported an 8-year-old girl withhomocystinuria-megaloblastic anemia due to defects in cobalaminmetabolism, cblE type (236270) in whom megaloblastic anemia was detectedat 11 weeks of age. She had nystagmus, hyperkinesis, and developmentaldelay that resolved with age. Severe hyperhomocysteinemia with normalmethionine levels was found and enzymatic and complementation studiesconfirmed the cobalamin E defect. The patient was homozygous for a140-bp insertion (903-904ins140). The insertion was caused by a T-to-Ctransition within intron 6 of the MTRR gene, which presumably leads toactivation of an exon splicing enhancer. Both the patients' parentsoriginated from the same geographic region, and the family historypointed to possible consanguinity. Wilson et al. (1999) identified this mutation in 2 patients.
.0007HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblE COMPLEMENTATION TYPE MTRR, SER454LEUIn a group of 9 patients of European origin withhomocystinuria-megaloblastic anemia due to defects in cobalaminmetabolism, cblE type (236270), Zavadakova et al. (2005) found a 1361C-Ttransition in the MTRR gene causing a ser454-to-leu (S454L) substitutionin 5 independent alleles, either in a homozygous state (2 patients) or aheterozygous state (1 patient). The S454L mutation had been found onlyin patients of Spanish or Portuguese ancestry, supporting the idea thatthis is an Iberian mutation. The 2 homozygous patients were mildlyaffected without severe neurologic involvement.
References
1Bosco, 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, 2003.200312923861
2Doolin, 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, 2002.200212375236
3Hobbs, 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, 2000.200010930360
4James, 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, 1999.199910500018
5Leclerc, 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, 1998.19989501215
6O'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, 2005.200515979034
7Wilson, 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, 1999.199910484769
8Wilson, 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, 1999.199910484769
9Wilson, 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, 1999.199910444342
10Yamada, 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, 2006.200616769880
11Zavadakova, 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, 2005.200515714522
12Zavadakova, 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, 2003.200312555939
Contributors
Cassandra L. Kniffin- updated: 07/26/2006
Patricia A. Hartz- updated: 07/19/2006
Victor A. McKusick- updated: 01/06/2006
Victor A. McKusick- updated: 04/01/2005
Victor A. McKusick- updated: 10/07/2003
Ada Hamosh- updated: 09/18/2003
Victor A. McKusick- updated: 12/23/2002
Victor A. McKusick- updated: 09/25/2000
Victor A. McKusick- updated: 10/25/1999
Creation date
Victor A. McKusick04/24/1998
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