Biochemistry and molecular genetics of cystathionine beta-synthase deficiency.

Homocysteine is an independent risk factor for arteriosclerotic disease. Deficiency of cystathionine beta-synthase (CBS) is the major cause of inherited homocysteinemia. The CBS gene is 25-30 kbp long and encodes a subunit of 63 kDa. The active form of the enzyme is a homotetramer that contains one heme and one pyridoxal 5'-phosphate per each subunit. It can also bind 1 mol of S-adenosylmethionine per mol of subunit. To date, an analysis of 205 homocystinuric alleles has been performed and 64 mutations found. The best studied, relatively "homogeneous" patient populations are those of Ireland, Holland, and Italy. While the overall frequency of the two most frequent mutations is 24% for I278T and 31% for G307S, the breakdown between the countries varies greatly. For instance, the B6-nonresponsive G307S mutation accounts for > 70% alleles in Ireland and B6-responsive I278T mutation on the continent approaches 45%. In conclusion, further research is needed to define the mutations in individual countries to facilitate screening and genotype/phenotype correlations. Future biochemical studies will likely elucidate the role of heme in the enzyme and the tertiary structure of CBS.