Betaine-homocysteine methyltransferase (BHMT): Genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans

Elevated homocysteine levels have been associated with arteriosclerosis and thrombosis. Hyperhomocysteinemia is caused by altered functioning of enzym es of its metabolism due to either inherited or acquired factors. Betaine-h omocysteine methyltransferase (BHMT) serves, next to methionine synthase, a s a facilitator of methyl group donation for remethylation of homocysteine into methionine, and reduced functioning of BHMT could theoretically result in elevated homocysteine levels. Recently, the genomic sequence of the BHM T gene was published. Mutation analysis may reveal mutations of the BHMT ge ne that could lead to hyperhomocysteinemia. In the present study we perform ed genomic sequencing of the BHMT gene of 16 vascular patients with hyperho mocysteinemia and detected three mutations in the coding region of this gen e. The first was an amino acid substitution of glycine to serine (G199S), w hich was found only in the heterozygous state. The second mutation was a su bstitution of glutamine to arginine (Q239R), and the last mutation was an a mino acid substitution of glutamine to histidine (Q406H). The latter was al so found only in the heterozygous state. The relevance of these mutations w as tested in a study group, which consists of 190 cases with vascular disea se and 601 controls. The influence of these three mutations on homocysteine levels was investigated. None of the three mutations led to significantly changed homocysteine levels. In addition, no differences in genotype distri bution between cases and controls mere found. So far, our results provide n o evidence for a role of defective BHMT functioning in hyperhomocysteinemia or subsequently in vascular disease. (C) 2000 Academic Press.