HIGH PREVALENCE OF A MUTATION IN THE CYSTATHIONINE BETA-SYNTHASE GENE

We found that a mutation preciously described by Sebastio et al., invo lving a GS-bp insertion in the coding region of exon 8 of the cystathi onine-beta-synthase (CBS) gene in a single patient with homocystinuria , is highly prevalent. In our control population, 11.7% (9/77) of the individuals were hetorozygous carriers of this mutation. In contrast t o the previous report, which assumed that the 68-bp insertion introduc ed a premature-termination codon and resulted in a nonfunctional CBS e nzyme, we found that the presence of this mutation is not associated w ith hyperhomocysteinemia. Assay of CBS activity in transformed lymphoc ytes from individuals who were heterozygous or homozygous for this mut ation showed normal activity. Furthermore, reverse-transcription-PCR s howed that individuals carrying this mutation have normal size mRNA. O ur results suggest that the insertion creates an alternate splicing si te, which eliminates not only the inserted intronic sequences but also the T833C mutation associated with this insertion. The net result is the generation of both quantitatively and qualitatively normal mRNA an d CBS enzyme. Although the mutation does not seem to affect the activi ty of the CBS enzyme, the prevalence is somewhat increased in patients with premature coronary-artery disease, although the difference is no t statistically significant.