2 NOVEL MUTATIONS IN THE CYSTATHIONINE BETA-SYNTHASE GENE OF HOMOCYSTINURIC PATIENTS

Background: The continued identification of new mutations in the cysta thionine beta-synthase (CBS) gene is important in correlating the geno type/phenotype of patients with classic homocystinuria and in assessin g whether heterozygosity of CBS deficiency is an important cause of mi ld hyperhomocysteinemia, an independent risk factor for occlusive vasc ular diseases. Methods and Results: Single-strand conformational polym orphism and direct nucleotide sequencing were used to detect two novel mutations in the CBS gene of three homocystinuric patients from two u nrelated families, The first mutation, a G-to-A transition at nucleoti de 1316 in exon 12, results in an amino acid substitution of arginine by glutamine at codon 439. The second mutation is a G-to-A transition at nucleotide 1109 in exon 10 and results in an amino acid substitutio n of cysteine by tyrosine at codon 370: All three patients are apparen tly compound heterozygotes, with one of the two novel mutations on one allele and the T833C mutation on the other allele. Conclusions: The a bsence of the G(1316)A and G(1109)A mutations in 216 control alleles d emonstrates that these two novel mutations do not represent common pol ymorphisms, but rather are responsible for the defective CBS enzyme ac tivities encoded by one of the two alleles of the CBS gene in each of the two families.