MOLECULAR ANALYSIS OF PATIENTS AFFECTED BY HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY - REPORT OF A NEW MUTATION IN EXON-8 AND A DELETION IN INTRON-11

Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is an inborn metabolic disorder of sulphur amino acids, inherited as an autosomal recessive trait (McKusick 236200). Main biochemical and clinical findings are homocystinuria with hypermethioninaemia, mental retardation, dislocated optic lenses, skeletal anomalies and premature thromboembolic disease. Two forms of the disease can be distinguished on the basis of patients' responsiveness to treatment with pyridoxine, the precursor of CBS cofactor: a more severe clinical picture is present in non-responsive patients than in responsive ones. Human CBS cDNA has been cloned and mapped to chromosome 21q22.3 (Kraus et al 1993). In CBS-deficient patients some mutations have been characterized; the most frequent are 1278T due to a T-to-C transition (T833C) in exon 8 (Kozich and Kraus 1992), G307S due to a G-to-A transition (G(919)A) in exon 8 (Hu et al 1993), and the splice site mutation A(1224-2)C, causing the skipping of the entire exon 12 (Kozich and Kraus 1992). Here we report two independent patients showing a novel mutation in exon 8 and a 49 bp deletion located in intron 11, respectively. In addition we have tested the occurrence of four relatively common mutations (A114V, I278T, G307S, A(1224-2)C) in 16 homocystinuric families of South European origin.