A MISSENSE MUTATION (1278T) IN THE CYSTATHIONINE BETA-SYNTHASE GENE PREVALENT IN PYRIDOXINE-RESPONSIVE HOMOCYSTINURIA, AND ASSOCIATED WITH MILD CLINICAL PHENOTYPE

Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder characterized by homocystinuria and multisystem clinical dis ease. Patients responsive to pyridoxine usually have a milder clinical phenotype than do nonresponsive patients, and we studied the molecula r pathology of this disorder in an attempt to understand the molecular basis of the clinical variation. We previously reported a T833C trans ition in exon 8 causing a substitution of threonine for isoleucine at codon 278 (I278T). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patient s with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-non responsive patients. Two pyridoxine-responsive patients are homezygous and five are heterozygous for I278T. We have now observed the I278T m utation in 41% (9 of 22) of the independent alleles in pyridoxine-resp onsive patients of varied ethnic backgrounds. In two of the compound h eterozygotes we identified a novel mutation (G139R and E144K) in the o ther allele. The finding that the two patients who are homozygous for I278T have only ectopia lentis and mild bone demineralization suggests that this mutation is associated with both in vivo pyridoxine respons iveness and mild clinical disease. Compound heterozygous patients who have one copy of this missense mutation are likely to retain some degr ee of pyridoxine responsiveness.