STRUCTURAL ORGANIZATION OF THE HUMAN DIHYDROPYRIMIDINE DEHYDROGENASE GENE

Deficiency of the pyrimidine catabolic enzyme, dihydropyrimidine dehyd rogenase (DPD), has been shown to be responsible for a pharmacogenetic syndrome in which administration of 5-fluorouracil is associated with severe and potentially life-threatening toxicity. Following the recen t availability of the cDNA for DPD, there were initial reports of seve ral molecular defects (point mutations, deletions due to exon skipping ) that were suggested as a potential molecular basis for DPD deficienc y, even before the complete physical structure of the DPD gene was kno wn, To understand the mechanism responsible for DPD deficiency, we hav e determined the genomic structure and organization of the human DPD g ene. The gene is approximately 150 kb in length, and it consists of 23 exons, ranging in size from 69 to 1404 bp. The sequences of intronic regions flanking the exon boundaries have been determined. The physica l map of the DPD gene should permit development of rapid assays to det ect point mutations or small deletions in the DPD gene associated with 5-fluorouracil toxicity.