High prevalence of a mutation in the cystathionine β-synthase gene

• Published in: American journal of human genetics Vol. 59; no. 6; pp. 1262 - 1267
• Main Authors: TSAI, M. Y, BIGNELL, M, SCHWICHTENBERG, K, HANSON, N. Q
• Format: Journal Article
• Language: English
• Published: Chicago, IL University of Chicago Press 01.12.1996
• Subjects: Adult; Aminoacid disorders; Biological and medical sciences; Coronary Disease - blood; Coronary Disease - enzymology; Coronary Disease - genetics; Cystathionine beta-Synthase - genetics; DNA Mutational Analysis; Errors of metabolism; Female; Homocysteine - blood; Humans; Male; Medical sciences; Metabolic diseases; Middle Aged; Mutagenesis, Insertional; Polymerase Chain Reaction; Human; Thiol; Genetic inheritance; Prevalence; Enzyme; Deficiency; Cardiovascular disease; Metabolic diseases; Risk; Lyases; Cystathionine β-synthase; Coronary heart disease; Epidemiology; Sulfur containing aminoacid; Atherosclerosis; Genetics; Mutation; Carbon-oxygen lyases; Hydro-lyases
• ISSN: 0002-9297; 1537-6605

We found that a mutation previously described by Sebastio et al., involving a 68-bp insertion in the coding region of exon 8 of the cystathionine-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 heterozygous carriers of this mutation. In contrast to the previous report, which assumed that the 68-bp insertion introduced a premature-termination codon and resulted in a nonfunctional CBS enzyme, we found that the presence of this mutation is not associated with hyperhomocysteinemia. Assay of CBS activity in transformed lymphocytes from individuals who were heterozygous or homozygous for this mutation showed normal activity. Furthermore, reverse-transcripion-PCR showed that individuals carrying this mutation have normal size mRNA. Our results suggest that the insertion creates an alternate splicing site, 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 and CBS enzyme. Although the mutation does not seem to affect the activity of the CBS enzyme, the prevalence is somewhat increased in patients with premature coronary-artery disease, although the difference is not statistically significant.