Two Novel Mutations in the Cystathionine β-synthase Gene of Homocystinuric Patients

Background: The continued identification of new mutations in the cystathionine β-synthase (CBS) gene is important in correlating the genotype/phenotype of patients with classic homocystinuria and in assessing whether heterozygosity of CBS deficiency is an important cause of mild hyperhomocysteinemia, an independent risk factor for occlusive vascular diseases. Methods and Results: Single-strand conformational polymorphism and direct nucleotide sequencing were used to detect two novel mutations in the CBS gene of three homocystinuric patients from two unrelated families. The first mutation, a G-to-A transition at nucleotide 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 substitution of cysteine by tyrosine at codon 370: All three patients are apparently compound heterozygotes, with one of the two novel mutations on one allele and the T₈₃₃C mutation on the other allele. Conclusions: The absence of the G₁₃₁₆A and G₁₁₀₉A mutations in 216 control alleles demonstrates that these two novel mutations do not represent common polymorphisms, but rather are responsible for the defective CBS enzyme activities encoded by one of the two alleles of the CBS gene in each of the two families.