Four novel mutations at the cystathionine β-synthase locus causing homocystinuria

We describe four new mutations in the cystathionine β-synthase gene: three point mutations localized in exons 3, 9 and 10 and one mutation in exon 12 which results in stop codon. Homocystinuria due to cystathionine β-synthase (CBS, EC.4.2.1.22) deficiency (McKusick 236200), is the most common autosomal recessive inborn error of the transsulphuration pathway. Homocystinuric patients exhibit mental retardation, psychotic behaviour, dislocated lenses, vascular disease, osteoporosis and skeletal abnormalities. About 50% of affected subjects show biochemical improvements when treated with pyridoxine, the precursor of the CBS cofactor pyridoxal 5′-phosphate. The severity of the disease varies among the patients: pyridoxine-responsive patients usually have a milder clinical phenotype than pyridoxine-nonresponsive patients. Human CBS cDNA has been cloned and its complete sequence, with minor differences in the coding region, has been published by three teams (Chasse et al 1995; Kraus et al 1993; Kruger and Cox 1994). The screening for mutations in homocystinuric patients has led to the identification of more than 50 mutations (Aral et al 1997; Dawson et al 1996; De Franchis et al 1994; Gallagher et al 1995; Hu et al 1993; Kluijtmans et al 1995; Kozich et al 1993; Kozich and Kraus 1992; Kraus 1994; Marble et al 1994; Shih et al 1995; Sebastio et al 1995; Sperandeo et al 1995). Two mutations are found to be most prevalent: (a) I278T only in pyridoxine-responsive patients; (b) G307S mutation, the leading cause of homocystinuria in Ireland and in patients of ‘Celtic origin’ (Gallagher et al 1995). We describe here four novel mutations at the CBS locus.