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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

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1437-4315
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Volume 386, Issue 4

Issues

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

André B.P. Van Kuilenburg
  • Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, P.O. Box 22700, NL-1100 DE Amsterdam, The Netherlands
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/ Rutger Meinsma
  • Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, P.O. Box 22700, NL-1100 DE Amsterdam, The Netherlands
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/ Eva Beke
  • Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, P.O. Box 22700, NL-1100 DE Amsterdam, The Netherlands
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/ Barbara Bobba
  • University of Turin, Department of Pediatrics, Child Neuropsychiatry Unit, I-10126 Turin, Italy
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/ Patrizia Boffi
  • University of Turin, Department of Pediatrics, Child Neuropsychiatry Unit, I-10126 Turin, Italy
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/ Gregory M. Enns
  • Stanford University, Division of Medical Genetics, Department of Pediatrics, Stanford, CA 94305-5208, USA
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/ David R. Witt / Doreen Dobritzsch
  • Karolinska Institute, Department of Medical Biochemistry and Biophysics, S-17177 Stockholm, Sweden
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Published Online: 2005-07-05 | DOI: https://doi.org/10.1515/BC.2005.038

Abstract

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

About the article

Corresponding author


Received: November 5, 2004

Accepted: February 3, 2005

Published Online: 2005-07-05

Published in Print: 2005-04-01


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

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