Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterized by thymine-uraciluria in homozygous deficient patients. Cancer patients with a partial deficiency of DPD are at risk of developing severe life-threatening toxicities after the administration of 5-fluorouracil. Thus, identification of novel disease-causing mutations is of the utmost importance to allow screening of patients at risk. In eight patients presenting with a complete DPD deficiency, a considerable variation in the clinical presentation was noted. Whereas motor retardation was observed in all patients, no patients presented with convulsive disorders. In this group of patients, nine novel mutations were identified including one deletion of two nucleotides [1039-1042delTG] and eight missense mutations. Analysis of the crystal structure of pig DPD suggested that five out of eight amino acid exchanges present in these patients with a complete DPD deficiency, Pro86Leu, Ser201Arg, Ser492Leu, Asp949Val and His978Arg, interfered directly or indirectly with cofactor binding or electron transport. Furthermore, the mutations Ile560Ser and Tyr211Cys most likely affected the structural integrity of the DPD protein. Only the effect of the Ile370Val and a previously identified Cys29Arg mutation could not be readily explained by analysis of the three-dimensional structure of the DPD enzyme, suggesting that at least the latter might be a common polymorphism. Our data demonstrate for the first time the possible consequences of missense mutations in the DPD gene on the function and stability of the DPD enzyme.
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May 08 2002
Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure Available to Purchase
André B.P. van KUILENBURG;
André B.P. van KUILENBURG
1
∗Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands
1To whom correspondence should be addressed (e-mail [email protected]).
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Doreen DOBRITZSCH;
Doreen DOBRITZSCH
†Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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Rutger MEINSMA;
Rutger MEINSMA
∗Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands
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Janet HAASJES;
Janet HAASJES
∗Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands
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Hans R. WATERHAM;
Hans R. WATERHAM
∗Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands
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Malgorzata J.M. NOWACZYK;
Malgorzata J.M. NOWACZYK
‡Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
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George D. MAROPOULOS;
George D. MAROPOULOS
§Department of Chemical Pathology, General Children's Hospital of Athens, Athens, Greece
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Guido HEIN;
Guido HEIN
∥Children's Hospital Dortmund, Dortmund, Germany
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Hermann KALHOFF;
Hermann KALHOFF
∥Children's Hospital Dortmund, Dortmund, Germany
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Jean M. KIRK;
Jean M. KIRK
¶Dept. of Paediatric Biochemistry, Royal Hospital for Sick Children, Edinburgh, Scotland, U.K.
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Holger BAASKE;
Holger BAASKE
∗∗Klinik am Eichert Göppingen, Göppingen, Germany
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Anne AUKETT;
Anne AUKETT
††City Hospital NHS Trust, Birmingham, U.K.
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John A. DULEY;
John A. DULEY
‡‡Purine Research Laboratory, Guy's Hospital, London Bridge, London, U.K.
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Kate P. WARD;
Kate P. WARD
§§Airedale General Hospital, Keighley, West Yorkshire, U.K.
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Ylva LINDQVIST;
Ylva LINDQVIST
†Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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Albert H. van GENNIP
Albert H. van GENNIP
∗Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands
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Publisher: Portland Press Ltd
Received:
December 12 2001
Revision Received:
February 18 2002
Accepted:
March 04 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 364 (1): 157–163.
Article history
Received:
December 12 2001
Revision Received:
February 18 2002
Accepted:
March 04 2002
Citation
André B.P. van KUILENBURG, Doreen DOBRITZSCH, Rutger MEINSMA, Janet HAASJES, Hans R. WATERHAM, Malgorzata J.M. NOWACZYK, George D. MAROPOULOS, Guido HEIN, Hermann KALHOFF, Jean M. KIRK, Holger BAASKE, Anne AUKETT, John A. DULEY, Kate P. WARD, Ylva LINDQVIST, Albert H. van GENNIP; Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. Biochem J 15 May 2002; 364 (1): 157–163. doi: https://doi.org/10.1042/bj3640157
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