Identification of novel point mutations in the dihydropyrimidine dehydrogenase gene

Dihydropyrimidine dehydrogenase deficiency (McKusick 274270) is an autosomal recessive disorder leading to thymine-uraciluria. Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2) catalyses the first and rate-limiting step in the catabolism of uracil, thymine and the analogue 5-fluorouracil. Patients do not exhibit a characteristic clinical phenotype, although in about half the cases with a complete or near-complete deficiency of the enzyme convulsive disorders are observed (Berger et al 1984; van Gennip et al 1989, 1994; Braakhekke et al 1987). In patients with a nearly complete enzyme defect, the initial diagnosis can be made on the presence of large amounts of both thymine and uracil in the patient's body fluids, whereas the diagnosis can be confirmed by measurement of the enzyme activity in either peripheral mononuclear cells or fibroblasts (Van Kuilenburg et al 1996). The recent cloning of the dihydropyrimidine dehydrogenase cDNA now allows detection of the defect at the molecular level (Yokota et al 1994). We previously described a 165 base pair deletion in mRNA-derived cDNA, caused by exon skipping, in a patient with a complete deficiency of DPD (Meinsma et al 1995). Analysis of the flanking intron sequences revealed that exon skipping was due to a G → A point mutation in the invariant GT splice donor sequence in the intron downstream of the skipped exon (Vreken et al 1996). So far, no other mutations in the DPD gene have been described. We now report a new frameshift mutation (ΔC1897) and two missense mutations (T85C and G2658A) leading to amino acid substitutions C29R and R886H.