Vitamin B12 Deficiency

 

 

MTR and Vitamin B12 Deficiency

 

Methionine synthase is the main enzyme that allows for the regeneration of methionine from homocysteine, which is achieved by the addition of the methyl donor from methyl B12 to homocysteine, to form methionine. The reaction can be written as:

Homocysteine + MethylCo(III)B12 + methionine synthase => methionine + *Co(I)B12.

 

Regeneration of MethylCo(III)B12 also involves the enzyme wherein 5-methyl-tetrahydrofolate donates its methyl group to *Co(I)B12. The reaction can be written as:

5-methyl-tetrahydrofolate + *Co(I)B12 + methionine synthase => tetrahydrofolate + MethylCo(III)B12.

 

The enzyme is unusual in that the main co-factor is cobalamin, and the concentration of available cobalamin determines the rate of activity of the enzyme. Thus, as vitamin B12 levels drop the rate of the enzyme drops dramatically. This is regardless of which SNP(s) the enzyme has.

It is not known how the activity of the enzyme is altered in various SNP alleles, nor is it known what the effect of multiple SNPs have on enzymatic activity.

 

 

 

Mutations in the MTR gene.

There many different mutations in the MTR gene, and nearly everyone has one or more, variants of the gene, which may or may not affect the function and hence the rate of synthesis of methionine of/by the MTR enzyme. Data on what the effect of the various single nucleotide polymorphisms (SNPs) on enzyme function is rather sparse.

 

MTR rs10925260, a rarely typed SNP has been associated with a higher risk of neural tube defects (Pangilinan etal, 2014)

 

MTR rs1805087 (C2756A>G) was not found to be associated with higher risk for NTD (Pangilinan etal, 2014) and was more common in preterm births (Wang etal, 2015). MTR 2756AA had a lower risk of death following gastric cancer (Zhao etal, 2015). The SNP also was associated with elevated homocysteine levels and elevated risk of coronary artery disease (Masud and Bagai, 2017). Further 2756GG was associated with azospermia in male infertility (Lee etal 2006). There was an apparent selection against 2765GG, such that its incidence was lower in low B12 levels such that the frequency of the allele is also relatively rare (r=0.14) (Miriuka etal, 2005: personal observations), suggesting a strong selection against the SNP in low B12 levels.

 

Other MTR SNPs include rs2275568, rs1206026 and rs1206057, s3820571, rs3768142,  rs2275566, rs1092523 and rs1092525, however we have not been able to find any publications indicating that these SNPs are associative for any particular condition.

 

Early publications on MTR, in which the cblG terminology was used showed reduced methylation of down to 3 to 25% of normal in patients with various MTR mutations (Watkins and Rosenblatt, 1988). Effectively this would translate to a vitamin B12 level that was only 3 to 25% of normal optimal levels. The comparative rates methionine synthesis between controls and 3 persons with MTR mutations (cblG) are graphically presented below.

 

 

MTR and Autism

Multiple SNPs in MTR are seen in children with autism, however, the frequency is not highly enough to be considered causative for the reduced level of vitamin B12 seen in these children.

There appear to be several "linked" SNPs, such as rs2275568, rs1206026 and rs1206057, and rs3820571, rs3768142,  and rs2275566, however it is not known what effect the multiple SNPs have on enzymatic function, nor could we find any publications on same.

 

References

Pangilinan etal, Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects BMC Med Genet. 2014 PMID25293959

Wang etal Association between SNPs in genes involved in folate metabolism and preterm birth risk Genet Mol Res 2015 14: 850-9

Zhao etal Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: large and comprehensive study. Oncotarget 2015 6:9564-76

Masad and Baqai The communal relation of MTHFR, MTR, ACE gene polymorphisms and hyperhomocysteinemia as conceivable risk of coronary artery disease Appl Physol Nutr Metab 2017 42: 1009-1014

Lee etal Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Hum Reprod 2006 21: 3162-70

Miriuka etal Genetic polymorphisms predisposing to hyperhomocysteinemia in cardiac transplant patients. Tranpl Int. 2005 18: 29-35

Watkins, D, Rosenblatt, DS. Genetic heterogeneity among patients with methylcobalamin deficiency. J. Clin Invest, 81, 1690-1694

 

 


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