Recent insights into the molecular genetics of the homocysteine metabolism

The homocysteine plasma level is determined by non-genetic and genetic fact ors. In recent years evidence has accumulated that the total homocysteine p lasma level of patients under different forms of renal replacement therapy is influenced by a common mutation at nucleotide position 677 of the gene c oding for 5,10-methylenetetrahydrofolate reductase (MTHFR 677C-->T). Furthe rmore, compound heterozygosity for the 677T allele and a novel A-->C polymo rphism at nucleotide position 1298 of MTHFR is suggested to correlate with a decrease of folate plasma concentrations. Because polymorphisms of genes coding for proteins involved in the metabolism of homocysteine may contribu te to elevated total homocysteine plasma concentrations, molecular genetic analyses of the homocysteine pathways experienced a drift towards screening for candidate genes with a putative relationship to total homocysteine pla sma levels. One example is the cloning of the FOLR1 gene coding for the fol ate-binding protein (Folbp1), which has recently been inactivated in mice, thus representing ng an elegant model to investigate the consequence on the homocysteine metabolism. Furthermore, the recent characterization of the C UBN gene encoding the intrinsic factor-vitamin B-12 receptor (cubilin) prov ides a basis to identify the causative mutations in patients suffering from a hereditary syndrome of hyperhomocysteinemia that presents with megalobla stic anemia and proteinuria. This review focuses on recent insights into th e molecular genetics of MTHFR, FOLR1, and CUBN, and their relationships to the metabolism of the amino acid homocysteine.