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Methionine synthase reductase also known as MSR is an enzyme that in humans is encoded by the MTRR gene.^[5]^[6]

Function

Methionine is an essential amino acid required for protein synthesis and one-carbon metabolism. Its synthesis is catalyzed by the enzyme methionine synthase. Methionine synthase eventually becomes inactive due to the oxidation of its cob(I)alamin cofactor. Methionine synthase reductase regenerates a functional methionine synthase via reductive methylation. It is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases.^[6]

MTRR Gene

MTRR
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2QTL, 2QTZ
Identifiers
Aliases	MTRR, MSR, cblE, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase
External IDs	OMIM: 602568 MGI: 1891037 HomoloGene: 11419 GeneCards: MTRR
Gene location (Human)
Chr.	Chromosome 5 (human)
End	7,906,025 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	68,730,268 bp
RNA expression pattern
	Top expressed in
	endothelial cell; ; pancreatic ductal cell; ; upper lobe of left lung; ; biceps brachii; ; kidney tubule; ; right ventricle; ; monocyte; ; rectum; ; gastrocnemius muscle; ; right uterine tube;
	Top expressed in
	renal corpuscle; ; yolk sac; ; medullary collecting duct; ; spermatocyte; ; ureter; ; skeletal muscle tissue; ; morula; ; vas deferens; ; knee joint; ; lens;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	FMN binding; NADPH-hemoprotein reductase activity; flavin adenine dinucleotide binding; FAD binding; protein binding; NADP binding; NADPH binding; oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor; oxidoreductase activity; (Methionine synthase) reductase; [methionine synthase reductase activity];
Cellular component	cytosol; cytoplasm;
Biological process	cobalamin metabolic process; cellular amino acid biosynthetic process; methionine biosynthetic process; DNA methylation; methionine metabolic process; homocysteine catabolic process; folic acid metabolic process; negative regulation of cystathionine beta-synthase activity; S-adenosylmethionine cycle; homocysteine metabolic process; sulfur amino acid metabolic process; methylation;
	Sources:Amigo / QuickGO
Orthologs
	4552
	210009
	ENSG00000124275
	ENSMUSG00000034617
	Q9UBK8
	Q8C1A3
	NM_002454; NM_024010
	NM_172480; NM_001308475
	NP_002445; NP_076915; NP_001351369; NP_001351370; NP_001351371
	NP_001295404; NP_766068
	Wikidata
View/Edit Human	View/Edit Mouse

Aliases of MTRR gene

5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase
MSR
[Methionine Synthase]- Cobalamin Methyltransferase (Cob(II)Alamin Reducing)
Methionine Synthase Reductase, Mitochondrial
EC 1.16.1.8
CblE

Introduction

The Methionine Synthase Reductase (MTRR) gene primarily acts in the reductive regeneration of cob(I)alamin (vitamin B12).^[7] Cob(I)alamin is a cofactor that maintains activation of the methionine synthase enzyme (MTR) Methionine synthase, linking folate and methionine metabolism. Donation of methyl groups from folate are utilized for cellular and DNA methylation, influencing epigenetic inheritance.^[7]^[8]^[9]

Mapping

The gene was mapped to human chromosome 5. Gene specific primer pairs resulted in PCR amplification of a product matched by size to a hybrid-mapping panel containing only chromosome 5 as its human genetic material.^[5] The product DNA sequence matched pre-established gene markers specific to this chromosome. Exact gene cytogenic position was determined by mapping to an artificial chromosomal construct containing the gene via fluorescence in situ hybridization.^[5] The exact MTRR gene location was mapped to 5p15.3-p15.2.^[5]

Structure

The MTRR gene is associated with a family of electron transferases known as the Ferredoxin-NADP(+) reductase (FNR) family. Found in 15 primates and over 16 tissues in humans, MTRR is 34 kb long.^[10] The gene comprises 15 exons and includes numerous cytolosic mitochondrial mRNA isoforms. Multiple cofactor binding sites assist in the maintenance of MTR activity via reductive remethylation. All binding domains involve selective and non-covalent interactions except the flavodoxin_1 domain.^[10]

MTRR co-factor binding sites

Flavodoxin-1 domain

Flavoproteins are ubiquitous biocatalysts binding specific redox active prosthetic groups. The domain is associated with electron transfer proteins and used in electron transport systems.^[10] The cofactor flavin-mononucleotide (FMN) is bound non-covalently to the domain, which is functionally interchangeable with iron-sulfur constituted proteins regulating electron transfer or ferredoxins.^[10]

FAD-binding

Flavin adenine dinucleotide in its oxidized form, FAD is a cofactor of flavoprotein oxidoreductase enzymes. Flavoprotein pyridine nucleotide cytochrome reductases, including FAD catalyse the interchange of reducing equivalents (H+ or electrons). Initial electron donors and final electron acceptors comprise single electron carriers and two electron carrying nicotinamide dinucleotides respectively.^[10]

NAD binding 1

Evolutionary conserved protein domain corresponding to oxidoreductase activity. NAD binding catalyzes redox reactions to alter the oxidation state of metal ions, using NADP+ as an electron acceptor.^[10]

Methionine synthase reductase activity

Involved in the reductive remethylation of cob(II)alamin using S-adenosylhomocysteine as a methyl donor. Catalyses the reaction:

[methionine synthase]- cob(II)alamin + NADPH + H+ + S-adenosylmethionine → [methionine synthase]-methylcob(I)alamin + S-adenosylhomocysteine + NADP+.^[10]

Aquacobalamin reductase (NADPH) activity

Belongs to the oxidoreductase family, oxidizing metal ions with NADP+ acting as an electron acceptor. Uses FAD as a cofactor when catalyzing the following reaction:

2cob(II)alamin + NADP+ 2aquacob(III)alamin + NADPH + H+.^[10]

Flavin adenine dinucleotide binding

Interacts with the cofactor or prosthetic group, FAD of flavoproteins and contains a flavin moiety in the form of FAD or FMN (flavin mononucleotide). The domain non-covalently binds oxidized FAD or its reduced form, hydroquinone (FADH2).^[10]

FMN binding

Flavin mononucleotide binding domain interacts with a coenzyme of flavoprotein oxidoreductase enzymes, FMN.^[10]

NADP binding

Nicotinamide adenine dinucleotide phosphate is a coenzyme present in redox and biosynthetic reactions. The domain binds NADP in its oxidised or reduced forms as NADP+ or NADPH respectively.^[10]

NADPH binding

Involves a non-covalent and selective interaction with the reduced form of NADP, NADPH.^[10]

NADPH-hemoprotein reductase activity

The domain is associated with the oxidoreductase family and acts on NADH or NADPH, using a heme protein as an electron acceptor. Requires FAD and FMN as cofactors to catalyse the reaction:

NADPH + H+ + n oxidised hemoprotein = NADP+ + n reduced hemoprotein.^[10]

Protein binding

Binding domain involved in the interaction with proteins or protein complexes.^[10]

Function

Methionine synthase reductase (MTRR) is primarily involved in the reductive methylation of homocysteine to methionine, utilizing methylcob(I)alamin as an intermediate methyl carrier.^[8] Methionine is an essential amino acid in mammals, necessary for protein synthesis and one carbon metabolism. In its activated form, S-adenosylmethionine acts as a methyl donor in biological transmethylation reactions and as a propylamine donor in polyamine synthesis.^[8] A major product of methionine demethylation is homocysteine. Remethylation of homocysteine occurs via a cobalamin dependent enzyme, methionine synthase (MTR).^[8] The folate cycle is linked to homocysteine metabolism via MTR.^[11] Circulating blood folate (5-methyl tetrahydrofolate, 5-MTHF) donates methyl groups to MTR to be utilized in cellular methylation. A methyl cobalt bond of the intermediary methyl carrier, methlycob(III)alamin is cleaved heterolytically producing cobalamin in its highly reactive oxidation state as cob(I)alamin. The enzyme bound cob(I)alamin cofactor of the MTR enzyme functions as a methyl carrier between 5-MTHF and homocysteine.^[8] Cob(I)alamin is oxidised to cob(II)alamin about once every 100 methyl transfer cycles, rendering the cob(I)alamin-MTR-enzyme complex inactive.^[12] Reactivation of this enzyme complex occurs through reductive remethylation by MTRR, utilizing S-adenosylmethionine as a methyl donor. MTR reactivation can also be NADPH dependent involving two redox proteins, soluble cytochrome b5 and reductase 1. However, this pathway is responsible for a minor role in reactivation, whilst MTRR remains a major contributor in this reductive reactivation.

Biological processes influenced by MTRR include: sulfur amino acid metabolic process, DNA methylation, methionine metabolic process, methionine biosynthetic process, methylation, S-adenosylmethionine cycle, homocysteine catabolic process, folic acid metabolic process, oxidation-reduction process and negative regulation of cystathionine beta-synthase activity.^[8]^[11]

Polymorphisms

Known pathogenic mutations

(MTRR):c.66A>G – Polymorphism resulting in isoleucine conversion to methionine at codon 22. This mutation is found within and affects the FMN binding domain.^[13]
(MTRR):c.524C>T – Serine to leucine substitution at codon 175. Benign mutation associated with impaired intracellular cobalamin metabolism disorders.^[14]
(MTRR):c.1049A>G – Lysine to arginine substitution at codon 350.^[15]
(MTRR):c.1349C>G – Proline to arginine substitution at codon 450. Prevalence associated with abnormal intracellular cobalamin metabolism disorders.^[16]
(MTRR):c.903+469T>C – Deep intronic insertion between exons 6 and 7 (r.903_904ins140). Threonine to cysteine change resulting in activation of an exon splicing enhancer in intron 6.^[17]
(MTRR):c.1361C>T – Rare polymorphism involving serine to leucine substitution at codon 454. Known as the Iberian mutation, prevalent in homocystinuria megaloblastic anemia due to impaired cobalamin metabolism. Mainly three different halotypes (GTACG, GCACA, GCACG) from the deamination of methyl cytosine in different chromosomes.^[18]
(MTRR):c.1459G>A – Involves glycine to arginine substitution at codon 487. Conserved in MTRR and found to occur within the FAD binding domain. Pathogenicity associated with inborn genetic diseases.^[19]
(MTRR):c.1573C>T – Arginine substitution with a premature termination codon at codon 525.^[20]
(MTRR):c.1622_1623dupTA – Results in formation of a premature termination codon. Pathogenicity associated with CblE type of homocystinuria.^[21]
(MTRR):r.1462_1557del96 – Associated with splicing of exon 11 due to a 7 base pair deletion. A large deletion of this mutant allele results in the absence of a c-terminus in the FAD binding domain. Pathogenicity associated with CblE type of homocystinuria.^[21]
(MTRR):c.1953-6_1953-2del5 – Novel mutation associated with CblE type of homocystinuria. Unstable mRNA arising from this mutant results in an absence of mRNA required for translation, producing pathogenicity.^[21]

Mutations involved in the formation of premature termination codons result in truncated mutated proteins if translated.^[21] Mutants exhibit an absence of FAD/NADPH binding domains and unstable mRNA due to nonsense mediated decay (NMD). NMD is not present in (MTRR):c.1573C>T or (MTRR):c.1622_1623dupTA polymorphisms.^[21] The (MTRR):c.903+469T>C variant is also associated with the formation of premature termination codons.^[21]

Other mutations

(MTRR):c.1911G>A ¬– Benign synonymous mutation (alanine to alanine) at codon 637. Associated with disorders of cobalamin metabolism.^[22]

Clinical significance

Single nucleotide polymorphisms (SNPs) in the MTRR gene impair MTR activity, resulting in elevated homocysteine levels due to compromised methylation to methionine. Elevated homocysteine levels are associated with birth defects in addition to pregnancy complications, cardiovascular disease, cancer,^[23] megaloblastic anemia, Alzheimer’s diseases and cognitive dysfunction in the elderly.^[24] Presence of the mutant variant (66A>G) is associated with significantly lower, up to 4 fold, plasma cobalamin and folate levels in cardiac transplant patients.^[23] A consequent decrease in S-adenosylmethionine availability results in DNA hypomethylation. Low folate limits one carbon metabolism and homocysteine metabolism as vitamin B12 interacts with folate in this pathway.^[24] Additionally, this mutation is associated with an increased risk in type 2 diabetes.^[25]

Cancer

Specific SNPs are associated with an elevated risk of lung cancer and interact with folate dietary intake in this etiology. The (MTRR):c.66A>G mutation relates to a significant increase in the risk of lung cancer. When co-expressed with the polymorphism (MTR): 2756A>G, lung cancer risk is further increased in a dose dependent manner.^[24] Correlation between this polymorphism and increased risk of lung cancer is present with low folate intake and high vitamin B12, suggesting a B12 independent mechanism of action.^[24] This mutation is also associated with an increased risk in colorectal cancer, ^[26]^[27]^[28]^[29] acute lymphoblastic leukemia,^[30] bladder cancer,^[31] cervical intraepithelial neoplasia, non-Hodgkin lymphoma^[32] and oesophageal squamous cell carcinoma.^[33]

CblE type of homocystinuria

Remethylation of homocysteine to methionine by MTR requires the derivative of cobalamin, methylcobalamin. Cobalamin metabolism is initiated by the endocytosis of cobalamin bound to the plasma protein transcobalamin (II). Cleavage of this complex produces free cobalamin, translocating from lysosome to cytoplasm. Conversion can occur to 5’-deoxyadenosylcobalamin (AdoCbl) activating the mitochrondrial enzyme methylmalonly coenzyme A mutase or to methylcobalamin (MeCbl).^[34] An error in cobalamin metabolism resulting in decreased MeCbl and unaffected AdoCbl is characteristic of the CblE type of homocystinuria.^[34] This complementation is rare with autosomal recessive inheritance. The inherited methionine synthase functional deficiency corresponds to a defect in the reducing system required to activate the MTR enzyme. Symptoms of this condition comprise developmental retardation, megaloblastic anemia, homocystinuria, hypomethioninemia, cerebral atrophy and hyperhomocysteinemia.^[34] However, hypomethioninemia remains an inconsistent symptom. Decreased MeCbl alongside normal cobalamin uptake is suggestive of decreased intracellular methionine biosynthesis. Occurring mainly in childhood, 15 pathogenic mutations can be associated with CblE type homocystinuria.^[35] Additionally, vascular abnormalities are associated with this defect.^[36] Impaired reduction of an oxidised cobalt atom in the active site of MTR is associated with this condition, where enzyme activity can be corrected with reducing agents.^[35] Rare polymorphisms related to this disease include (MTRR):c.1459G>A, (MTRR):c.1623-1624insTA and (MTRR):c.903+469T>C.^[35] These mutations, excluding (MTRR):c.1459G>A result in a frame shift, producing premature termination codons.^[35] As consequent products are distant from normal, mutant mRNA arises and nonsense mediated decay (FMN) is initiated.^[35] The large insertion of 903_904ins140 corresponding to 903+469T>C is most prevalent in CblE pathology. The activation of an enhanced splicer within intron 6 is incomplete, producing small quantities of normal spliced MTRR mRNA.^[35] Prenatal diagnosis of this condition is possible using [14C] methyltetrahydrofolate.^[35] Mutation analysis in native chorionic villi and [14C] formate in amino acids within these villi or cultured amniocytes is indicative of the CblE defect.^[35] Additionally, macrocytic anemia is a typical feature of the CblE defect and can be corrected though OH-Cobalamin administration or folate supplementation.^[35]

Coronary artery disease

Homocysteine, a sulfur based amino acid is the main product of methionine demethylation. Elevated homocysteine is an independent risk factor for cardiovascular disease and inversely correlated to consumed vitamin B12/B6 and folate levels.^[37] Homocysteine methylation to methionine is catalyzed by MTR, resulting in appropriate intracellular levels of methionine and tetrahydrofolate, alongside non-toxic homocysteine levels. The GG phenotype promotes the development of premature coronary artery disease (CAD) independent of hyperhomocysteinemia.^[37] Hyperhomocysteinemia is associated with cerebral, coronary and peripheral atherosclerotic pathology as it promotes endothelial cell dysfunction, platelet adhesion and vascular smooth muscle cell proliferation.^[36] DNA damage and homocysteine levels are proportional to CAD severity. Micronucleus frequency in human lymphocytes, dependent on homocysteine levels increases reactive oxygen species and uracil incorporation in DNA methylation, promoting genetic alterations and point mutations.^[36] The (MTRR):c.66A>G, polymorphism containing chromosome is prone to fragmentation. This chromosomal loss or global DNA hypomethylation results in under condensation of pericentromeric heterochromatin, micronucleus formation and elevated risks of aneuploidy.^[36] Co-expression of this mutation and the 677T polymorphism in methionine tetrahydrofolate reductase (MTHFR) Methylenetetrahydrofolate reductase act to further the extent of DNA damage.^[36]

Hypomethylation due to impaired methylation up regulates atherosclerotic susceptible genes whilst down regulating atherosclerosis protective genes.^[36] This abnormality is present during the atherosclerotic pathology, increasing transcriptional activity of platelet derived growth factor (PDGF) and promoting smooth muscle cell proliferation.^[36]

Neural tube defects

Spina bifida

MTRR requires vitamin B12 for maintenance of the methyl synthase reaction whilst folate is needed for normal synthesis of nucleotide precursors. These ensure normal DNA synthesis and cellular methylation reactions.^[8] Chronic folate or methyl deficiencies are thereby linked to abnormal DNA methylation. The 66A>G polymorphism is up-regulated in neural tube defects and increases the risk of spina bifida by two-fold.^[38] Homozygosis for this mutation is an established maternal risk factor for spina bifida especially with low intracellular vitamin B12^[39] in the circulation or amniotic fluid.^[13] Vitamin B12 is reflected by plasma methylmalonic acid (MMA), an elevation in which indicates impaired B12 uptake or metabolism.^[8] A raised MMA combined with the MTRR mutation corresponds to a 5-fold increase in spina bifida.^[8] The mechanism of action of this polymorphism is through the mother, hence there is no preferential transmission of this mutation from parent to child. Abnormal MTRR binding to the MTR-cob(I)alamin-enzyme complex down regulates the rate of homocysteine methylation. Consequent decreases in methionine and S-adenosylmethionine negatively affect DNA, gene and protein methylation, all of which are involved in neural tube closure.^[8] Increased proliferation during neurulation decreases the availability of DNA nucleotides. As these are unable to be replaced due to impaired DNA methylation and nucleotide formation, consequent disturbed neurulation results in the formation of neural tube defects.^[9] Co-expression of this mutation with the 677C>T MTHFR polymorphism furthers the risk of spina bifida compared to an independent acting 66A>G mutation.^[8]

Down syndrome

Trisomy 21 or down syndrome is the most common human chromosomal anomaly arising from abnormal chromosomal segregation in meiosis.^[7]^[9]^[40] The condition can occur during anaphase in meiosis(I) marking oocyte maturation before ovulation and/or during anaphase in meiosis (II) signifying fertilization.^[9] Metabolic impact during these stages is furthered by low vitamin B12.^[41] Methylation of homocysteine to methionine is affected, primarily by the (MTRR):c.66A>G polymorphism. Chronic homocysteine elevation increases s-adenosyl-L-homocysteine levels, consequently inhibiting methyltransferase activity and promoting DNA hypomethylation.^[7]^[42] Mothers homozygous for this mutation (GG phenotype) are at a greater risk of having a child with down syndrome compared to heterozygotes (GA phenotype).^[41] Geographically, Irish populations are more likely to be homogenous whilst north American populations are commonly heterogeneous, resulting in a greater incidence of the polymorphism in the former group.^[9]^[41] The homozygous mutant allele promotes DNA hypomethylation and meiotic non-disjunction, increasing the risk of down syndrome.^[43] This polymorphism correlates to a 2.5 fold risk increase independently and a 4 fold increase in risk when co-expressed with the 677C>T MTHFR mutation.^[9] Combination with the MTR2756A>G genetic polymorphism further elevates down syndrome risk.^[9]^[42]^[44]

References

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^ Lin J, Spitz MR, Wang Y, Schabath MB, Gorlov IP, Hernandez LM; et al. (2004). "Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study". Carcinogenesis. 25 (9): 1639–47. doi:10.1093/carcin/bgh175. PMID 15117811. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Skibola CF, Forrest MS, Coppedé F, Agana L, Hubbard A, Smith MT; et al. (2004). "Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma". Blood. 104 (7): 2155–62. doi:10.1182/blood-2004-02-0557. PMID 15198953. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Stolzenberg-Solomon RZ, Qiao YL, Abnet CC, Ratnasinghe DL, Dawsey SM, Dong ZW; et al. (2003). "Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China". Cancer Epidemiol Biomarkers Prev. 12 (11 Pt 1): 1222–6. PMID 14652285. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c Watkins D, Rosenblatt DS (1988). "Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG". J Clin Invest. 81 (6): 1690–4. doi:10.1172/JCI113507. PMC 442612. PMID 3384945.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilová K, Kozich V; et al. (2002). "CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families". J Inherit Metab Dis. 25 (6): 461–76. PMID 12555939. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d ^e ^f ^g Botto N, Andreassi MG, Manfredi S, Masetti S, Cocci F, Colombo MG; et al. (2003). "Genetic polymorphisms in folate and homocysteine metabolism as risk factors for DNA damage". Eur J Hum Genet. 11 (9): 671–8. doi:10.1038/sj.ejhg.5201024. PMID 12939653. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b Brown CA, McKinney KQ, Kaufman JS, Gravel RA, Rozen R (2000). "A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease". J Cardiovasc Risk. 7 (3): 197–200. PMID 11006889.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Shaw GM, Lu W, Zhu H, Yang W, Briggs FB, Carmichael SL; et al. (2009). "118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects". BMC Med Genet. 10: 49. doi:10.1186/1471-2350-10-49. PMC 2700092. PMID 19493349. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ Balduino Victorino D, de Godoy MF, Goloni-Bertollo EM, Pavarino ÉC (2014). "Genetic polymorphisms involved in folate metabolism and maternal risk for down syndrome: a meta-analysis". Dis Markers. 2014: 517504. doi:10.1155/2014/517504. PMC 4269293. PMID 25544792.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ Muthuswamy, Srinivasan; Agarwal, Sarita (2016). "Do the MTHFR gene polymorphism and Down syndrome pregnancy association stands true? A case–control study of Indian population and meta-analysis". Egyptian Journal of Medical Human Genetics. 17 (1): 87–97. doi:10.1016/j.ejmhg.2015.08.003. ISSN 1110-8630.
^ ^a ^b ^c O'Leary VB, Parle-McDermott A, Molloy AM, Kirke PN, Johnson Z, Conley M; et al. (2002). "MTRR and MTHFR polymorphism: link to Down syndrome?". Am J Med Genet. 107 (2): 151–5. PMID 11807890. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b Martínez-Frías ML, Pérez B, Desviat LR, Castro M, Leal F, Rodríguez L; et al. (2006). "Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes: is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?". Am J Med Genet A. 140 (9): 987–97. doi:10.1002/ajmg.a.31203. PMID 16575899. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Bosco P, Guéant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F; et al. (2003). "Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome". Am J Med Genet A. 121A (3): 219–24. doi:10.1002/ajmg.a.20234. PMID 12923861. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Pogribna M; et al. (2001). "Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect". Am J Med Genet. 103 (2): 128–32. PMID 11568918. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

References

External links

GeneReviews/NCBI/NIH/UW entry on Disorders of Intracellular Cobalamin Metabolism

@@ Line 6: / Line 6: @@
 [[Methionine]] is an essential [[amino acid]] required for protein synthesis and [[one-carbon metabolism]]. Its synthesis is catalyzed by the enzyme [[methionine synthase]]. Methionine synthase eventually becomes inactive due to the oxidation of its [[cobalamin|cob(I)alamin]] [[Cofactor (biochemistry)|cofactor]]. Methionine synthase reductase regenerates a functional methionine synthase via reductive methylation. It is a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases.<ref name="entrez"/>
+=MTRR Gene=
-== Clinical significance ==
+==Aliases of ''MTRR'' gene==
+* 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase
+* MSR
+* [Methionine Synthase]- Cobalamin Methyltransferase (Cob(II)Alamin Reducing)
+* Methionine Synthase Reductase, Mitochondrial
+* EC 1.16.1.8
+* CblE
+==Introduction==
+The Methionine Synthase Reductase (''MTRR'') gene primarily acts in the reductive regeneration of cob(I)alamin (vitamin B12).<ref name="WangQiao2008">{{cite journal|last1=Wang|first1=Shao-shuai|last2=Qiao|first2=Fu-yuan|last3=Feng|first3=Ling|last4=Lv|first4=Juan-juan|title=Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China|journal=Journal of Zhejiang University SCIENCE B|volume=9|issue=2|year=2008|pages=93–99|issn=1673-1581|doi=10.1631/jzus.B0710599}}</ref> Cob(I)alamin is a cofactor that maintains activation of the methionine synthase enzyme (MTR) [[Methionine synthase]], linking folate and methionine metabolism. Donation of methyl groups from folate are utilized for cellular and DNA methylation, influencing epigenetic inheritance.<ref name="WangQiao2008"/><ref name="van der Lindenden Heijer2006">{{cite journal|last1=van der Linden|first1=Ivon J. M.|last2=den Heijer|first2=Martin|last3=Afman|first3=Lydia A.|last4=Gellekink|first4=Henkjan|last5=Vermeulen|first5=Sita H. H. M.|last6=Kluijtmans|first6=Leo A. J.|last7=Blom|first7=Henk J.|title=The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida|journal=Journal of Molecular Medicine|volume=84|issue=12|year=2006|pages=1047–1054|issn=0946-2716|doi=10.1007/s00109-006-0093-x}}</ref><ref name="pmid10930360">{{cite journal| author=Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ et al.| title=Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. | journal=Am J Hum Genet | year= 2000 | volume= 67 | issue= 3 | pages= 623-30 | pmid=10930360 | doi=10.1086/303055 | pmc=1287522 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10930360  }} </ref>
+==Mapping==
+The gene was mapped to human chromosome 5. Gene specific primer pairs resulted in PCR amplification of a product matched by size to a hybrid-mapping panel containing only chromosome 5 as its human genetic material.<ref name="pmid9501215"/> The product DNA sequence matched pre-established gene markers specific to this chromosome. Exact gene cytogenic position was determined by mapping to an artificial chromosomal construct containing the gene via fluorescence in situ hybridization.<ref name="pmid9501215"/> The exact MTRR gene location was mapped to 5p15.3-p15.2.<ref name="pmid9501215"/>
+==Structure==
+The MTRR gene is associated with a family of electron transferases known as the Ferredoxin-NADP(+) reductase (FNR) family. Found in 15 primates and over 16 tissues in humans, MTRR is 34 kb long.<ref name="UniProt">{{cite web |url=http://www.uniprot.org/uniprot/Q9UBK8+ |title=MTRR - Methionine synthase reductase - Homo sapiens (Human) - MTRR gene & protein |format= |work= |accessdate=2017-09-16}} </ref> The gene comprises 15 exons and includes numerous cytolosic mitochondrial mRNA isoforms. Multiple cofactor binding sites assist in the maintenance of MTR activity via reductive remethylation. All binding domains involve selective and non-covalent interactions except the flavodoxin_1 domain.<ref name="UniProt"/>
+===MTRR co-factor binding sites===
+===Flavodoxin-1 domain===
+Flavoproteins are ubiquitous biocatalysts binding specific redox active prosthetic groups. The domain is associated with electron transfer proteins and used in electron transport systems.<ref name="UniProt"/> The cofactor flavin-mononucleotide (FMN) is bound non-covalently to the domain, which is functionally interchangeable with iron-sulfur constituted proteins regulating electron transfer or ferredoxins.<ref name="UniProt"/>
+====FAD-binding====
+Flavin adenine dinucleotide in its oxidized form, FAD is a cofactor of flavoprotein oxidoreductase enzymes. Flavoprotein pyridine nucleotide cytochrome reductases, including FAD catalyse the interchange of reducing equivalents (H+ or electrons). Initial electron donors and final electron acceptors comprise single electron carriers and two electron carrying nicotinamide dinucleotides respectively.<ref name="UniProt"/>
+====NAD binding 1====
+Evolutionary conserved protein domain corresponding to oxidoreductase activity. NAD binding catalyzes redox reactions to alter the oxidation state of metal ions, using NADP+ as an electron acceptor.<ref name="UniProt"/>
+====Methionine synthase reductase activity====
+Involved in the reductive remethylation of cob(II)alamin using S-adenosylhomocysteine as a methyl donor. Catalyses the reaction:
+[methionine synthase]- cob(II)alamin + NADPH + H+ + S-adenosylmethionine → [methionine synthase]-methylcob(I)alamin + S-adenosylhomocysteine + NADP+.<ref name="UniProt"/>
+====Aquacobalamin reductase (NADPH) activity====
+Belongs to the oxidoreductase family, oxidizing metal ions with NADP+ acting as an electron acceptor. Uses FAD as a cofactor when catalyzing the following reaction:
+cob(II)alamin + NADP+      2aquacob(III)alamin + NADPH + H+.<ref name="UniProt"/>
+====Flavin adenine dinucleotide binding====
+Interacts with the cofactor or prosthetic group, FAD of flavoproteins and contains a flavin moiety in the form of FAD or FMN (flavin mononucleotide). The domain non-covalently binds oxidized FAD or its reduced form, hydroquinone (FADH2).<ref name="UniProt"/>
+====FMN binding====
+Flavin mononucleotide binding domain interacts with a coenzyme of flavoprotein oxidoreductase enzymes, FMN.<ref name="UniProt"/>
+====NADP binding====
+Nicotinamide adenine dinucleotide phosphate is a coenzyme present in redox and biosynthetic reactions. The domain binds NADP in its oxidised or reduced forms as NADP+ or NADPH respectively.<ref name="UniProt"/>
+====NADPH binding====
+Involves a non-covalent and selective interaction with the reduced form of NADP, NADPH.<ref name="UniProt"/>
+====NADPH-hemoprotein reductase activity====
+The domain is associated with the oxidoreductase family and acts on NADH or NADPH, using a heme protein as an electron acceptor. Requires FAD and FMN as cofactors to catalyse the reaction:
+NADPH + H+ + n oxidised hemoprotein = NADP+ + n reduced hemoprotein.<ref name="UniProt"/>
+====Protein binding====
+Binding domain involved in the interaction with proteins or protein complexes.<ref name="UniProt"/>
+==Function==
+Methionine synthase reductase (MTRR) is primarily involved in the reductive methylation of homocysteine to methionine, utilizing methylcob(I)alamin as an intermediate methyl carrier.<ref name="van der Lindenden Heijer2006"/> Methionine is an essential amino acid in mammals, necessary for protein synthesis and one carbon metabolism. In its activated form, S-adenosylmethionine acts as a methyl donor in biological transmethylation reactions and as a propylamine donor in polyamine synthesis.<ref name="van der Lindenden Heijer2006"/> A major product of methionine demethylation is homocysteine. Remethylation of homocysteine occurs via a cobalamin dependent enzyme, methionine synthase (MTR).<ref name="van der Lindenden Heijer2006"/>  The folate cycle is linked to homocysteine metabolism via MTR.<ref name="El-MaarriZhang2013">{{cite journal|last1=El-Maarri|first1=Osman|last2=Zhang|first2=Ti|last3=Lou|first3=Jiao|last4=Zhong|first4=Rong|last5=Wu|first5=Jing|last6=Zou|first6=Li|last7=Sun|first7=Yu|last8=Lu|first8=Xuzai|last9=Liu|first9=Li|last10=Miao|first10=Xiaoping|last11=Xiong|first11=Guanglian|title=Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature|journal=PLoS ONE|volume=8|issue=4|year=2013|pages=e59570|issn=1932-6203|doi=10.1371/journal.pone.0059570}}</ref> Circulating blood folate (5-methyl tetrahydrofolate, 5-MTHF) donates methyl groups to MTR to be utilized in cellular methylation. A methyl cobalt bond of the intermediary methyl carrier, methlycob(III)alamin is cleaved heterolytically producing cobalamin in its highly reactive oxidation state as cob(I)alamin. The enzyme bound cob(I)alamin cofactor of the MTR enzyme functions as a methyl carrier between 5-MTHF and homocysteine.<ref name="van der Lindenden Heijer2006"/> Cob(I)alamin is oxidised to cob(II)alamin about once every 100 methyl transfer cycles, rendering the cob(I)alamin-MTR-enzyme complex inactive.<ref name="pmid15514263">{{cite journal| author=Vaughn JD, Bailey LB, Shelnutt KP, Dunwoody KM, Maneval DR, Davis SR et al.| title=Methionine synthase reductase 66A->G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C->T variant. | journal=J Nutr | year= 2004 | volume= 134 | issue= 11 | pages= 2985-90 | pmid=15514263 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15514263  }} </ref> Reactivation of this enzyme complex occurs through reductive remethylation by MTRR, utilizing S-adenosylmethionine as a methyl donor. MTR reactivation can also be NADPH dependent involving two redox proteins, soluble cytochrome b5 and reductase 1. However, this pathway is responsible for a minor role in reactivation, whilst MTRR remains a major contributor in this reductive reactivation.
+Biological processes influenced by MTRR include: sulfur amino acid metabolic process, DNA methylation, methionine metabolic process, methionine biosynthetic process, methylation, S-adenosylmethionine cycle, homocysteine catabolic process, folic acid metabolic process, oxidation-reduction process and negative regulation of cystathionine beta-synthase activity.<ref name="van der Lindenden Heijer2006"/><ref name="El-MaarriZhang2013"/>
+[[File:Folate transport.png| thumb | Simplified overview of relationship between homocysteine and folate metabolism. Pathways highlight the metabolic processes and polymorphisms mentioned. MTRR, Methionine synthase reductase; MTHFR, methylene tetrahydrofolate reductase; MTR, methionine synthase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; THF, tetrahydrofolate; RFC, reduced folate carrier; 5methylTHF, 5 methyl tetrahydrofolate; Cob(I), cobalamin/cob(I)alamin/vitamin B12.]]
+==Polymorphisms==
+===Known pathogenic mutations===
+* (MTRR):c.66A>G – Polymorphism resulting in isoleucine conversion to methionine at codon 22. This mutation is found within and affects the FMN binding domain.<ref name="pmid10444342">{{cite journal| author=Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H et al.| title=A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. | journal=Mol Genet Metab | year= 1999 | volume= 67 | issue= 4 | pages= 317-23 | pmid=10444342 | doi=10.1006/mgme.1999.2879 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10444342  }} </ref>
+* (MTRR):c.524C>T – Serine to leucine substitution at codon 175. Benign mutation associated with impaired intracellular cobalamin metabolism disorders.<ref name="HassanKhattab2017">{{cite journal|last1=Hassan|first1=Fahima M.|last2=Khattab|first2=Ahmad A.|last3=Abo El Fotoh|first3=Wafaa Moustafa M.|last4=Zidan|first4=Reham S.|title=A66G  and  C524T  polymorphisms of methionine synthase reductase gene are linked to the development of acyanotic congenital heart diseases in Egyptian children|journal=Gene|volume=629|year=2017|pages=59–63|issn=03781119|doi=10.1016/j.gene.2017.07.081}}</ref>
+* (MTRR):c.1049A>G – Lysine to arginine substitution at codon 350.<ref name="c.1049A>G">{{cite web |url=https://www.ncbi.nlm.nih.gov/clinvar/RCV000126870/ |title=NM_002454.2(MTRR):c.1049A>G (p.Lys350Arg) AND not specified - ClinVar - NCBI |format= |work= |accessdate=2017-09-16}}</ref>
+* (MTRR):c.1349C>G – Proline to arginine substitution at codon 450. Prevalence associated with abnormal intracellular cobalamin metabolism disorders.<ref name="c.1349C>G">{{cite web |url=https://www.ncbi.nlm.nih.gov/clinvar/RCV000382140/ |title=NM_002454.2(MTRR):c.1349C>G (p.Pro450Arg) AND Disorders of Intracellular Cobalamin Metabolism - ClinVar - NCBI |format= |work= |accessdate=2017-09-16}}</ref>
+* (MTRR):c.903+469T>C – Deep intronic insertion between exons 6 and 7 (r.903_904ins140). Threonine to cysteine change resulting in activation of an exon splicing enhancer in intron 6.<ref name="pmid20120036">{{cite journal| author=Homolova K, Zavadakova P, Doktor TK, Schroeder LD, Kozich V, Andresen BS| title=The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria. | journal=Hum Mutat | year= 2010 | volume= 31 | issue= 4 | pages= 437-44 | pmid=20120036 | doi=10.1002/humu.21206 | pmc=3429857 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20120036  }} </ref>
+* (MTRR):c.1361C>T – Rare polymorphism involving serine to leucine substitution at codon 454. Known as the Iberian mutation, prevalent in homocystinuria megaloblastic anemia due to impaired cobalamin metabolism. Mainly three different halotypes (GTACG, GCACA, GCACG) from the deamination of methyl cytosine in different chromosomes.<ref name="c.1361C>T">{{cite web |url=https://www.ncbi.nlm.nih.gov/clinvar/variation/7033/ |title=NM_002454.2(MTRR):c.1361C>T (p.Ser454Leu) Simple - Variation Report - ClinVar - NCBI |format= |work= |accessdate=2017-09-16}}</ref>
+* (MTRR):c.1459G>A – Involves glycine to arginine substitution at codon 487. Conserved in MTRR and found to occur within the FAD binding domain. Pathogenicity associated with inborn genetic diseases.<ref name="c.1459G>A">{{cite web |url=https://www.ncbi.nlm.nih.gov/clinvar/RCV000210727/ |title=NM_002454.2(MTRR):c.1459G>A (p.Gly487Arg) AND Inborn genetic diseases - ClinVar - NCBI |format= |work= |accessdate=2017-09-16}}</ref>
+* (MTRR):c.1573C>T – Arginine substitution with a premature termination codon at codon 525.<ref name="c.1573C>T">{{cite web |url=https://www.ncbi.nlm.nih.gov/clinvar/23403790/ |title=NM_002454.2(MTRR):c.1573C>T (p.Arg525Ter) AND not provided - ClinVar - NCBI |format= |work= |accessdate=2017-09-16}}</ref>
+* (MTRR):c.1622_1623dupTA – Results in formation of a premature termination codon. Pathogenicity associated with CblE type of homocystinuria.<ref name="ZavadákováFowler2005">{{cite journal|last1=Zavadáková|first1=Petra|last2=Fowler|first2=Brian|last3=Suormala|first3=Terttu|last4=Novotna|first4=Zorka|last5=Mueller|first5=Peter|last6=Hennermann|first6=Julia B.|last7=Zeman|first7=Jiří|last8=Vilaseca|first8=M. Antonia|last9=Vilarinho|first9=Laura|last10=Gutsche|first10=Sven|last11=Wilichowski|first11=Ekkehard|last12=Horneff|first12=Gerd|last13=Kožich|first13=Viktor|title=cblEType of homocystinuria due to methionine synthase reductase deficiency: Functional correction by minigene expression|journal=Human Mutation|volume=25|issue=3|year=2005|pages=239–247|issn=10597794|doi=10.1002/humu.201}}</ref>
+* (MTRR):r.1462_1557del96 – Associated with splicing of exon 11 due to a 7 base pair deletion. A large deletion of this mutant allele results in the absence of a c-terminus in the FAD binding domain. Pathogenicity associated with CblE type of homocystinuria.<ref name="ZavadákováFowler2005"/>
+* (MTRR):c.1953-6_1953-2del5 – Novel mutation associated with CblE type of homocystinuria. Unstable mRNA arising from this mutant results in an absence of mRNA required for translation, producing pathogenicity.<ref name="ZavadákováFowler2005"/>
+Mutations involved in the formation of premature termination codons result in truncated mutated proteins if translated.<ref name="ZavadákováFowler2005"/>  Mutants exhibit an absence of FAD/NADPH binding domains and unstable mRNA due to nonsense mediated decay (NMD). NMD is not present in (MTRR):c.1573C>T or (MTRR):c.1622_1623dupTA polymorphisms.<ref name="ZavadákováFowler2005"/>  The (MTRR):c.903+469T>C variant is also associated with the formation of premature termination codons.<ref name="ZavadákováFowler2005"/>
+===Other mutations===
+* (MTRR):c.1911G>A ¬– Benign synonymous mutation (alanine to alanine) at codon 637. Associated with disorders of cobalamin metabolism.<ref name="c.1911G>A">{{cite web |url=https://www.ncbi.nlm.nih.gov/clinvar/variation/138302/ |title=NM_002454.2(MTRR):c.1911G>A (p.Ala637=) Simple - Variation Report - ClinVar - NCBI |format= |work= |accessdate=2017-09-16}}</ref>
+==Clinical significance==
+Single nucleotide polymorphisms (SNPs) in the MTRR gene impair MTR activity, resulting in elevated homocysteine levels due to compromised methylation to methionine. Elevated homocysteine levels are associated with birth defects in addition to pregnancy complications, cardiovascular disease, cancer,<ref name="WangLi2017">{{cite journal|last1=Wang|first1=Ping|last2=Li|first2=Sanqiang|last3=Wang|first3=Meilin|last4=He|first4=Jing|last5=Xi|first5=Shoumin|title=Association of MTRR A66G polymorphism with cancer susceptibility: Evidence from 85 studies|journal=Journal of Cancer|volume=8|issue=2|year=2017|pages=266–277|issn=1837-9664|doi=10.7150/jca.17379}}</ref> megaloblastic anemia, Alzheimer’s diseases and cognitive dysfunction in the elderly.<ref name="pmid16006998">{{cite journal| author=Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LM, Spitz MR et al.| title=Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis. | journal=Pharmacogenet Genomics | year= 2005 | volume= 15 | issue= 8 | pages= 547-55 | pmid=16006998 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16006998  }} </ref> Presence of the mutant variant (66A>G) is associated with significantly lower, up to 4 fold, plasma cobalamin and folate levels in cardiac transplant patients.<ref name="WangLi2017"/> A consequent decrease in S-adenosylmethionine availability results in DNA hypomethylation. Low folate limits one carbon metabolism and homocysteine metabolism as vitamin B12 interacts with folate in this pathway.<ref name="pmid16006998"/> Additionally, this mutation is associated with an increased risk in type 2 diabetes.<ref name="ZhiYang2016">{{cite journal|last1=Zhi|first1=Xueyuan|last2=Yang|first2=Boyi|last3=Fan|first3=Shujun|last4=Li|first4=Yongfang|last5=He|first5=Miao|last6=Wang|first6=Da|last7=Wang|first7=Yanxun|last8=Wei|first8=Jian|last9=Zheng|first9=Quanmei|last10=Sun|first10=Guifan|title=Additive Interaction of MTHFR C677T and MTRR A66G Polymorphisms with Being Overweight/Obesity on the Risk of Type 2 Diabetes|journal=International Journal of Environmental Research and Public Health|volume=13|issue=12|year=2016|pages=1243|issn=1660-4601|doi=10.3390/ijerph13121243}}</ref>
+===Cancer===
+Specific SNPs are associated with an elevated risk of lung cancer and interact with folate dietary intake in this etiology. The (MTRR):c.66A>G mutation relates to a significant increase in the risk of lung cancer. When co-expressed with the polymorphism (MTR): 2756A>G, lung cancer risk is further increased in a dose dependent manner.<ref name="pmid16006998"/> Correlation between this polymorphism and increased risk of lung cancer is present with low folate intake and high vitamin B12, suggesting a B12 independent mechanism of action.<ref name="pmid16006998"/> This mutation is also associated with an increased risk in colorectal cancer, <ref name="pmid12716294">{{cite journal| author=Matsuo K, Hamajima N, Hirai T, Kato T, Inoue M, Takezaki T et al.| title=Methionine Synthase Reductase Gene A66G Polymorphism is Associated with Risk of Colorectal Cancer. | journal=Asian Pac J Cancer Prev | year= 2002 | volume= 3 | issue= 4 | pages= 353-359 | pmid=12716294 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12716294  }} </ref><ref name="pmid14977639">{{cite journal| author=Sharp L, Little J| title=Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. | journal=Am J Epidemiol | year= 2004 | volume= 159 | issue= 5 | pages= 423-43 | pmid=14977639 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14977639  }} </ref><ref name="pmid20549016">{{cite journal| author=Wettergren Y, Odin E, Carlsson G, Gustavsson B| title=MTHFR, MTR, and MTRR polymorphisms in relation to p16INK4A hypermethylation in mucosa of patients with colorectal cancer. | journal=Mol Med | year= 2010 | volume= 16 | issue= 9-10 | pages= 425-32 | pmid=20549016 | doi=10.2119/molmed.2009.00156 | pmc=2935958 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20549016  }} </ref><ref name="MarchandDonlon2002">{{cite journal|last1=Marchand|first1=Loïc Le|last2=Donlon|first2=Timothy|last3=Hankin|first3=Jean H.|last4=Kolonel|first4=Laurence N.|last5=Wilkens|first5=Lynne R.|last6=Seifried|first6=Ann|title=B-vitamin intake, metabolic genes, and colorectal cancer risk (United States)|journal=Cancer Causes and Control|volume=13|issue=3|year=2002|pages=239–248|issn=09575243|doi=10.1023/A:1015057614870}}</ref> acute lymphoblastic leukemia,<ref name="pmid15159311">{{cite journal| author=Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Tognazzo S, Serino ML et al.| title=Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults. | journal=Cancer Epidemiol Biomarkers Prev | year= 2004 | volume= 13 | issue= 5 | pages= 787-94 | pmid=15159311 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15159311  }} </ref> bladder cancer,<ref name="pmid15117811">{{cite journal| author=Lin J, Spitz MR, Wang Y, Schabath MB, Gorlov IP, Hernandez LM et al.| title=Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study. | journal=Carcinogenesis | year= 2004 | volume= 25 | issue= 9 | pages= 1639-47 | pmid=15117811 | doi=10.1093/carcin/bgh175 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15117811  }} </ref> cervical intraepithelial neoplasia, non-Hodgkin lymphoma<ref name="pmid15198953">{{cite journal| author=Skibola CF, Forrest MS, Coppedé F, Agana L, Hubbard A, Smith MT et al.| title=Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. | journal=Blood | year= 2004 | volume= 104 | issue= 7 | pages= 2155-62 | pmid=15198953 | doi=10.1182/blood-2004-02-0557 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15198953  }} </ref> and oesophageal squamous cell carcinoma.<ref name="pmid14652285">{{cite journal| author=Stolzenberg-Solomon RZ, Qiao YL, Abnet CC, Ratnasinghe DL, Dawsey SM, Dong ZW et al.| title=Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China. | journal=Cancer Epidemiol Biomarkers Prev | year= 2003 | volume= 12 | issue= 11 Pt 1 | pages= 1222-6 | pmid=14652285 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14652285  }} </ref>
+===CblE type of homocystinuria===
+Remethylation of homocysteine to methionine by MTR requires the derivative of cobalamin, methylcobalamin. Cobalamin metabolism is initiated by the endocytosis of cobalamin bound to the plasma protein transcobalamin (II). Cleavage of this complex produces free cobalamin, translocating from lysosome to cytoplasm. Conversion can occur to 5’-deoxyadenosylcobalamin (AdoCbl) activating the mitochrondrial enzyme methylmalonly coenzyme A mutase or to methylcobalamin (MeCbl).<ref name="pmid3384945">{{cite journal| author=Watkins D, Rosenblatt DS| title=Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG. | journal=J Clin Invest | year= 1988 | volume= 81 | issue= 6 | pages= 1690-4 | pmid=3384945 | doi=10.1172/JCI113507 | pmc=442612 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3384945  }} </ref> An error in cobalamin metabolism resulting in decreased MeCbl and unaffected AdoCbl is characteristic of the CblE type of homocystinuria.<ref name="pmid3384945"/> This complementation is rare with autosomal recessive inheritance. The inherited methionine synthase functional deficiency corresponds to a defect in the reducing system required to activate the MTR enzyme. Symptoms of this condition comprise developmental retardation, megaloblastic anemia, homocystinuria, hypomethioninemia, cerebral atrophy and hyperhomocysteinemia.<ref name="pmid3384945"/> However, hypomethioninemia remains an inconsistent symptom. Decreased MeCbl alongside normal cobalamin uptake is suggestive of decreased intracellular methionine biosynthesis. Occurring mainly in childhood, 15 pathogenic mutations can be associated with CblE type homocystinuria.<ref name="pmid12555939">{{cite journal| author=Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilová K, Kozich V et al.| title=CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. | journal=J Inherit Metab Dis | year= 2002 | volume= 25 | issue= 6 | pages= 461-76 | pmid=12555939 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12555939  }} </ref> Additionally, vascular abnormalities are associated with this defect.<ref name="pmid12939653">{{cite journal| author=Botto N, Andreassi MG, Manfredi S, Masetti S, Cocci F, Colombo MG et al.| title=Genetic polymorphisms in folate and homocysteine metabolism as risk factors for DNA damage. | journal=Eur J Hum Genet | year= 2003 | volume= 11 | issue= 9 | pages= 671-8 | pmid=12939653 | doi=10.1038/sj.ejhg.5201024 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12939653  }} </ref> Impaired reduction of an oxidised cobalt atom in the active site of MTR is associated with this condition, where enzyme activity can be corrected with reducing agents.<ref name="pmid12555939"/> Rare polymorphisms related to this disease include (MTRR):c.1459G>A, (MTRR):c.1623-1624insTA and (MTRR):c.903+469T>C.<ref name="pmid12555939"/> These mutations, excluding (MTRR):c.1459G>A result in a frame shift, producing premature termination codons.<ref name="pmid12555939"/> As consequent products are distant from normal, mutant mRNA arises and nonsense mediated decay (FMN) is initiated.<ref name="pmid12555939"/> The large insertion of 903_904ins140 corresponding to 903+469T>C is most prevalent in CblE pathology. The activation of an enhanced splicer within intron 6 is incomplete, producing small quantities of normal spliced MTRR mRNA.<ref name="pmid12555939"/> Prenatal diagnosis of this condition is possible using [14C] methyltetrahydrofolate.<ref name="pmid12555939"/> Mutation analysis in native chorionic villi and [14C] formate in amino acids within these villi or cultured amniocytes is indicative of the CblE defect.<ref name="pmid12555939"/> Additionally, macrocytic anemia is a typical feature of the CblE defect and can be corrected though OH-Cobalamin administration or folate supplementation.<ref name="pmid12555939"/>
+===Coronary artery disease===
+Homocysteine, a sulfur based amino acid is the main product of methionine demethylation. Elevated homocysteine is an independent risk factor for cardiovascular disease and inversely correlated to consumed vitamin B12/B6 and folate levels.<ref name="pmid11006889">{{cite journal| author=Brown CA, McKinney KQ, Kaufman JS, Gravel RA, Rozen R| title=A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease. | journal=J Cardiovasc Risk | year= 2000 | volume= 7 | issue= 3 | pages= 197-200 | pmid=11006889 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11006889  }} </ref> Homocysteine methylation to methionine is catalyzed by MTR, resulting in appropriate intracellular levels of methionine and tetrahydrofolate, alongside non-toxic homocysteine levels.  The GG phenotype promotes the development of premature coronary artery disease (CAD) independent of hyperhomocysteinemia.<ref name="pmid11006889"/> Hyperhomocysteinemia is associated with cerebral, coronary and peripheral atherosclerotic pathology as it promotes endothelial cell dysfunction, platelet adhesion and vascular smooth muscle cell proliferation.<ref name="pmid12939653"/> DNA damage and homocysteine levels are proportional to CAD severity. Micronucleus frequency in human lymphocytes, dependent on homocysteine levels increases reactive oxygen species and uracil incorporation in DNA methylation, promoting genetic alterations and point mutations.<ref name="pmid12939653"/> The (MTRR):c.66A>G, polymorphism containing chromosome is prone to fragmentation. This chromosomal loss or global DNA hypomethylation results in under condensation of pericentromeric heterochromatin, micronucleus formation and elevated risks of aneuploidy.<ref name="pmid12939653"/> Co-expression of this mutation and the 677T polymorphism in methionine tetrahydrofolate reductase (MTHFR) [[Methylenetetrahydrofolate reductase]] act to further the extent of DNA damage.<ref name="pmid12939653"/>
+Hypomethylation due to impaired methylation up regulates atherosclerotic susceptible genes whilst down regulating atherosclerosis protective genes.<ref name="pmid12939653"/> This abnormality is present during the atherosclerotic pathology, increasing transcriptional activity of platelet derived growth factor (PDGF) and promoting smooth muscle cell proliferation.<ref name="pmid12939653"/>
+===Neural tube defects===
+====Spina bifida====
+MTRR requires vitamin B12 for maintenance of the methyl synthase reaction whilst folate is needed for normal synthesis of nucleotide precursors. These ensure normal DNA synthesis and cellular methylation reactions.<ref name="van der Lindenden Heijer2006"/> Chronic folate or methyl deficiencies are thereby linked to abnormal DNA methylation. The 66A>G polymorphism is up-regulated in neural tube defects and increases the risk of spina bifida by two-fold.<ref name="pmid19493349">{{cite journal| author=Shaw GM, Lu W, Zhu H, Yang W, Briggs FB, Carmichael SL et al.| title=118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. | journal=BMC Med Genet | year= 2009 | volume= 10 | issue=  | pages= 49 | pmid=19493349 | doi=10.1186/1471-2350-10-49 | pmc=2700092 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19493349  }} </ref> Homozygosis for this mutation is an established maternal risk factor for spina bifida especially with low intracellular vitamin B12<ref name="pmid25544792">{{cite journal| author=Balduino Victorino D, de Godoy MF, Goloni-Bertollo EM, Pavarino ÉC| title=Genetic polymorphisms involved in folate metabolism and maternal risk for down syndrome: a meta-analysis. | journal=Dis Markers | year= 2014 | volume= 2014 | issue=  | pages= 517504 | pmid=25544792 | doi=10.1155/2014/517504 | pmc=4269293 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25544792  }} </ref> in the circulation or amniotic fluid.<ref name="pmid10444342"/> Vitamin B12 is reflected by plasma methylmalonic acid (MMA), an elevation in which indicates impaired B12 uptake or metabolism.<ref name="van der Lindenden Heijer2006"/> A raised MMA combined with the MTRR mutation corresponds to a 5-fold increase in spina bifida.<ref name="van der Lindenden Heijer2006"/> The mechanism of action of this polymorphism is through the mother, hence there is no preferential transmission of this mutation from parent to child. Abnormal MTRR binding to the MTR-cob(I)alamin-enzyme complex down regulates the rate of homocysteine methylation. Consequent decreases in methionine and S-adenosylmethionine negatively affect DNA, gene and protein methylation, all of which are involved in neural tube closure.<ref name="van der Lindenden Heijer2006"/> Increased proliferation during neurulation decreases the availability of DNA nucleotides. As these are unable to be replaced due to impaired DNA methylation and nucleotide formation, consequent disturbed neurulation results in the formation of neural tube defects.<ref name="pmid10930360"/> Co-expression of this mutation with the 677C>T MTHFR polymorphism furthers the risk of spina bifida compared to an independent acting 66A>G mutation.<ref name="van der Lindenden Heijer2006"/>
+====Down syndrome====
+Trisomy 21 or down syndrome is the most common human chromosomal anomaly arising from abnormal chromosomal segregation in meiosis.<ref name="WangQiao2008"/><ref name="pmid10930360"/><ref name="MuthuswamyAgarwal2016">{{cite journal|last1=Muthuswamy|first1=Srinivasan|last2=Agarwal|first2=Sarita|title=Do the MTHFR gene polymorphism and Down syndrome pregnancy association stands true? A case–control study of Indian population and meta-analysis|journal=Egyptian Journal of Medical Human Genetics|volume=17|issue=1|year=2016|pages=87–97|issn=11108630|doi=10.1016/j.ejmhg.2015.08.003}}</ref> The condition can occur during anaphase in meiosis(I) marking oocyte maturation before ovulation and/or during anaphase in meiosis (II) signifying fertilization.<ref name="pmid10930360"/> Metabolic impact during these stages is furthered by low vitamin B12.<ref name="pmid11807890">{{cite journal| author=O'Leary VB, Parle-McDermott A, Molloy AM, Kirke PN, Johnson Z, Conley M et al.| title=MTRR and MTHFR polymorphism: link to Down syndrome? | journal=Am J Med Genet | year= 2002 | volume= 107 | issue= 2 | pages= 151-5 | pmid=11807890 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11807890  }} </ref> Methylation of homocysteine to methionine is affected, primarily by the (MTRR):c.66A>G polymorphism. Chronic homocysteine elevation increases s-adenosyl-L-homocysteine levels, consequently inhibiting methyltransferase activity and promoting DNA hypomethylation.<ref name="WangQiao2008"/><ref name="pmid16575899">{{cite journal| author=Martínez-Frías ML, Pérez B, Desviat LR, Castro M, Leal F, Rodríguez L et al.| title=Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes: is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome? | journal=Am J Med Genet A | year= 2006 | volume= 140 | issue= 9 | pages= 987-97 | pmid=16575899 | doi=10.1002/ajmg.a.31203 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16575899  }} </ref> Mothers homozygous for this mutation (GG phenotype) are at a greater risk of having a child with down syndrome compared to heterozygotes (GA phenotype).<ref name="pmid11807890"/> Geographically, Irish populations are more likely to be homogenous whilst north American populations are commonly heterogeneous, resulting in a greater incidence of the polymorphism in the former group.<ref name="pmid10930360"/><ref name="pmid11807890"/> The homozygous mutant allele promotes DNA hypomethylation and meiotic non-disjunction, increasing the risk of down syndrome.<ref name="pmid12923861">{{cite journal| author=Bosco P, Guéant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F et al.| title=Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. | journal=Am J Med Genet A | year= 2003 | volume= 121A | issue= 3 | pages= 219-24 | pmid=12923861 | doi=10.1002/ajmg.a.20234 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12923861  }} </ref> This polymorphism correlates to a 2.5 fold risk increase independently and a 4 fold increase in risk when co-expressed with the 677C>T MTHFR mutation.<ref name="pmid10930360"/> Combination with the MTR2756A>G genetic polymorphism further elevates down syndrome risk.<ref name="pmid10930360"/><ref name="pmid16575899"/><ref name="pmid11568918">{{cite journal| author=Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Pogribna M et al.| title=Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect. | journal=Am J Med Genet | year= 2001 | volume= 103 | issue= 2 | pages= 128-32 | pmid=11568918 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11568918}} </ref>
+==References==
+{{reflist}}
-Patients of the ''cblE'' complementation group of disorders of folate/cobalamin metabolism which results in [[homocystinuria]] are defective in reductive activation of methionine synthase.<ref name="entrez"/>
 == See also ==

MTRR (gene): Difference between revisions

Revision as of 07:03, 25 October 2017

Function

MTRR Gene

Aliases of MTRR gene

Introduction

Mapping

Structure

MTRR co-factor binding sites

Flavodoxin-1 domain

FAD-binding

NAD binding 1

Methionine synthase reductase activity

Aquacobalamin reductase (NADPH) activity

Flavin adenine dinucleotide binding

FMN binding

NADP binding

NADPH binding

NADPH-hemoprotein reductase activity

Protein binding

Function

Polymorphisms

Known pathogenic mutations

Other mutations

Clinical significance

Cancer

CblE type of homocystinuria

Coronary artery disease

Neural tube defects

Spina bifida

Down syndrome

References

See also

References

External links

Further reading