Table 3 A summary of the most frequently studied genes associated with vitamin B12 concentrations. The gene name, gene location and function of the most frequently studied genes associated with vitamin B12 concentrations are summarized in this table

Co-factors or regulators of co-factors essential for the transport of vitamin B12

Methylmalonic aciduria and homocystinuria, cblC type (MMACHC)

1p34.1

The MMACHC gene encodes a chaperone protein MMAACHC (cblC protein) which binds to vitamin B12 in the cytoplasm and appears to catalyze the reductive decyanation of cyanocobalamin into cob(II)alamin [11].

Transcobalamin 1 (TCN1)

11q12.1

It encodes a glycoprotein called Transcobalamin 1, also known as haptocorrin (HC), which binds to vitamin B12. It shields dietary vitamin B12 from the acidic environment of the stomach [12,18,19,20,21,22,108].

Fucosyltransferase 2 (FUT2)

19q13.33

It encodes the enzyme fucosyltransferase 2 (FUT2), which is involved in the synthesis of antigens of the Lewis blood group [5]. These antigens mediate the attachment of gastric pathogens to the gastric mucosa, which can affect the absorption of vitamin B12 [109].

Fucosyltransferase 6 (FUT6)

19p13.3

It encodes the enzyme fucosyltransferase 6 (FUT6), which is involved in forming Lewis associated antigens. These antigens attach gastric pathogens to the gastric mucosa. It has been shown that these gastric pathogens can reduce the absorption of vitamin B12 in the gut [43,44].

Transcobalamin 2 (TCN2)

22q12.2

It encodes a transport protein called transcobalamin 2 (TC), which binds to vitamin B12 within the enterocyte. The TC-B12 complex enters the portal circulation [59] and makes vitamin B12 available for cellular uptake in target tissues [49,110].

Membrane transporters that actively facilitates membrane crossing

Cubilin (CUBN)

10p13

It encodes the intestinal receptor Cubilin, which is expressed in the renal proximal tubule and intestinal mucosa [20,60,61]. Cubilin recognizes the vitaminB12-intrinsic factor complex, and binds to another protein called Amnionless to facilitate the entry of vitamin B12 into the intestinal cells [67].

ATP binding cassette subfamily D member 4 (ABCD4)

14q24.3

ABCD4 codes for an ABC transporter. It has been postulated that ABCD4 is involved in intracellular cobalamin processing [69], and is involved in transporting vitamin B12 from lysosomes to the cytosol. In the cytosol, vitamin B12 can be converted into methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) [70].

CD320 molecule (CD320)

19p13.2

It encodes the membrane receptor transcobalamin receptor (TCblR), which binds to the transcobalamin-vitamin B12 complex, and mediates the uptake of vitamin B12 into cells [72].

Proteins involved in the catalysis of enzymatic reactions in the one carbon cycle

Methylenetetrahydrofolate reductase (MTHFR)

1p36

MTHFR codes for a critical enzyme involved in homocysteine remethylation. MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in an irreversible reaction [74].

Methionine synthase reductase (MTRR)

5p15.31

This gene is responsible for maintaining adequate levels of activated vitamin B12 (methylcob(III)alamin), which maintains the enzyme methionine synthase in its active state [83].

Proteins involved in cell cycle regulation

Membrane-spanning 4-domains A3 (MS4A3)

11q12.1

MS4A3 encodes a protein involved as a hematopoietic cell cycle regulator [85]. MS4A3 gene may have a role in the cell-cycle regulation in the GI tract, thus affecting the renewal of intestinal and gastric epithelial cells, and absorption of vitamin B12 [86].

Mitochondrial protein

Methylmalonic aciduria (cobalamin deficiency) cb1A type (MMAA)

4q31

MMAA encodes a protein that may be involved in the translocation of vitamin B12 into the mitochondria [88]. In addition, MMAA could play an important role in the protection and reactivation of Methylmalonyl-coA mutase (MCM) in vitro [90].

Methylmalonyl-CoA mutase (MUT)

6p12.3

It encodes a Mitochondrial enzyme methylmalonyl-CoA mutase (MUT), which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. This isomerization requires vitamin B12 as a cofactor in the form of 5-prime-deoxyadenosylcobalamin (AdoCbl) [91].

Citrate lyase beta like (CLYBL)

13q32.3

It encodes a human mitochondrial enzyme, which is co-expressed with other co-enzymes in the mitochondrial B12 pathway [111].