Phenotypic studies in mice deficient in methylenetetrahydrofolate reductase and methionine synthase and their use as models for the pathophysiology of vitamin B12 deficiency
Abstract
Vitamin B12 and folate are substrates and cofactors for various enzymes involved in one carbon metabolism, which is important for DNA/RNA synthesis, amino acid interconversions and the methylation cycle. Two enzymes, methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS) play pivotal roles determining the direction of one carbon flow. MTHFR catalyzes the intracellular synthesis of 5-methyl-THF from 5, 10-methylene-THF. MS is one of two B12-dependent mammalian enzymes and catalyzes the remethylation of homocysteine to methionine and the concurrent demethylation of 5-methyl-THF to THF. MTHFR knockout mice show a variable phenotype with reduced survival. The MS knockout is early embryonic lethal. MTHFR/MS double knockout mice survive and have similar phenotypes as MTHFR null mice, which proved that the MS null mice die from extreme folate deficiency due to a methyl-folate trap. The common phenotypes shared by the MTHFR null and MS/MTHFR double null mice include retarded growth, hyperhomocysteinemia and a significantly low SAM/SAH ratio. Histological studies revealed cerebellum neuropathology and impaired male reproductive system in knockout mice. Microarray analysis showed that the expression of many genes was altered in MTHFR null and MS/MTHFR double null mice. Several subsets of induced or repressed genes encoded proteins involved in iron metabolism, lipid metabolism, SUMOylation, growth hormone/IGF pathway, stress responses, etc. We also studied some of…
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