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.—Gupta, S., Melnyk, S.B., Kruger, W.D. Cystathionine β‐synthase‐deficient mice thrive on a low‐methionine diet. FASEB J. 28, 781–790 (2014). www.fasebj.org