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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

12 Issues per year



Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function

André B.P. Van Kuilenburg1 / Rutger Meinsma2 / Eva Beke3 / Barbara Bobba4 / Patrizia Boffi5 / Gregory M. Enns6 / David R. Witt7 / Doreen Dobritzsch8









Corresponding author

Citation Information: Biological Chemistry. Volume 386, Issue 4, Pages 319–324, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2005.038, July 2005

Publication History

November 5, 2004
February 3, 2005
Published Online:


Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine, as well as of the widely used chemotherapeutic drug 5-fluorouracil (5FU). Analysis of the DPD gene (DPYD) in two patients presenting with complete DPD deficiency and the parents of an affected child showed the presence of three novel mutations, including one splice site mutation IVS11+1G→T and the missense mutations 731A→C (E244V) and 1651G→A (A551T). The G→T mutation in the invariant GT splice donor site flanking exon 11 (IVS11+1G→T) created a cryptic splice site within exon 11. As a consequence, a 141-bp fragment encoding the aminoacid residues 400–446 of the primary sequence of the DPD protein was missing in the mature DPD mRNA. Analysis of the crystal structure of pig DPD suggested that the E244V mutation might interfere with the electron flow between NADPH and the pyrimidine binding site of DPD. The A551T point mutation might prevent binding of the prosthetic group FMN and affect folding of the DPD protein. The identification of these novel mutations in DPYD will allow the identification of patients with an increased risk of developing severe 5FU-associated toxicity.

Keywords: dihydropyrimidine dehydrogenase; DPYD; 5-fluorouracil; pharmacogenetics; pyrimidines; thymine; uracil

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