Identification of Two Novel Mutations C79X and R235Q in the Dihydropyrimidine Dehydrogenase Gene in a Patient Presenting With Hematuria

Abstract

A patient with hematuria was shown to have thymine-uraciluria. The dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells was 0.16 nmol/mg/h; controls: 9.9 ± 2.8 nmol/mg/h. Analysis of DPYD showed that the patient was compound heterozygous for the novel mutations 237C > A (C79X) in exon 4 and 704G > A (R235Q) in exon 7. The nonsense mutation (C79X) leads to premature termination of translation and thus to a non-functional protein. Analysis of the crystal structure of pig DPD suggested that the R235Q mutation might interfere with the binding of FAD and the electron flow between the NADPH and the pyrimidine substrate site of DPD.

Keywords:

• Dihydropyrimidine dehydrogenase
• DPYD mutation
• 5-fluorouracil
• pharmacogenetics
• pyrimidines
• uracil
• thymine

This study was supported by the “Stichting Sacha Swarttouw-Hijmans,” the Wenner-Grenska Samfundet and the Swedish Cancer Foundation.

Notes

^a Mutation nomenclature according to den Dunnen and Antonarakis.^{[ 20 ]}

^b Data taken from van Kuilenburg et al.^{[ 21 ]}