Mthfr Knockout mouse models

Mthfr, the mouse ortholog of human MTHFR, encodes a FAD-dependent, NADPH-linked reductase that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the committed and effectively irreversible step that channels one-carbon units away from thymidylate and purine synthesis toward methionine synthase-mediated remethylation of homocysteine and thus toward S-adenosylmethionine production; the enzyme is allosterically inhibited by SAM through a carboxy-terminal regulatory domain, providing feedback control over methylation capacity. The common human C677T polymorphism produces a thermolabile Ala222Val protein with reduced FAD affinity and elevated homocysteine, especially under low folate intake. Homozygous nulls are viable but show hyperhomocysteinemia, altered DNA methylation, and developmental defects, so a humanized Ala222Val knockin is the design that models the common variant, whereas a null models severe deficiency and neural tube phenotypes. Because Bhmt provides a betaine-dependent remethylation bypass, dietary folate, choline, and betaine content must be specified as deliberately as the allele itself.

Global Mthfr deletion answers broad mechanism questions quickly. If timing or site matters, conditional alleles are a natural next step after the null is characterized.