MMACHC, also known as CblC, encodes a protein involved in intracellular vitamin B12 metabolism. Vitamin B12 obtained from the diet needs to be processed by MMACHC. This protein removes the upper-axial ligand of dietary B12 forms like hydroxocobalamin, methylcobalamin, etc., to yield cob(II)alamin, which is then delivered to two B12-dependent enzymes: cytosolic methionine synthase and mitochondrial methylmalonyl-CoA mutase. This process is crucial as it regenerates the coenzyme forms MeCbl and AdoCbl, which are essential for normal cellular function [1].

Mutations in MMACHC result in cblC disease, the most common inborn error of B12 metabolism. In cblC patients, vitamin B12 is absorbed but cells can't utilize it, leading to combined homocystinuria and methylmalonic aciduria due to lack of active MMACHC blocking cob(II)alamin formation [1]. In a mouse model with a gene-trap insertion in intron 1 of the Mmachc gene (Mmachc(Gt(AZ0348)Wtsi)), heterozygous mice had reduced MMACHC protein and elevated homocysteine and methylmalonic acid in blood. Homozygous Mmachc(Gt) embryos were not found after embryonic day 3.5 and were unable to generate giant cells in outgrowth assays, suggesting an early requirement for Mmachc in mouse development [2].

In conclusion, MMACHC is essential for the proper processing of vitamin B12 in cells, enabling the activation of key enzymes involved in metabolism. The Mmachc gene-trap mouse model has provided insights into the early role of Mmachc in development and the pathophysiology of cblC disease, highlighting the importance of this gene in normal biological processes and its implications in disease.