Cystathionine β-synthase-deficient mice thrive on a low-methionine diet

Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by elevated serum total homocysteine (tHcy). Previously, our laboratory developed a mouse model of CBS deficiency, TgI278T Cbs^-/- (abbreviated as Cbs^-/-), characterized by low weight, low adiposity, decreased Scd-1 expression, facial alopecia, and osteoporosis. To determine the potential benefit of a methionine-restricted diet (MRD), we fed Cbs^-/- and Cbs^+/- control mice either an MRD or a regular diet (RD) from weaning till 240 d of age. Cbs^-/- mice fed the MRD had a 77% decrease in tHcy, 28% increase in weight, 130% increase in fat mass, 82% increase in Scd-1 expression, and 10.6% increase in bone density and entirely lacked the alopecia phenotype observed in age-matched Cbs^-/- mice fed the RD. At the end of the study, Cbs^-/- mice fed the MRD were phenotypically indistinguishable from Cbs^+/- mice fed the RD. Notably, whereas the MRD diet was highly beneficial to Cbs ^-/- mice, it had nearly opposite effect on Cbs^+/- mice. These studies show that a low-methionine diet can correct the phenotypic consequences of loss of CBS and provide a striking example of how genotype and diet can interact to influence phenotype in mammals.