Elsevier

Genomics

Volume 51, Issue 3, 1 August 1998, Pages 391-400
Genomics

Regular Article
Characterization of the Human Dihydropyrimidine Dehydrogenase Gene

https://doi.org/10.1006/geno.1998.5379Get rights and content

Abstract

Dihydropyrimidine dehydrogenase (DPD) catabolizes endogenous pyrimidines and pyrimidine-based antimetabolite drugs. A deficiency in human DPD is associated with congenital thymine-uraciluria in pediatric patients and severe 5-fluorouracil toxicity in cancer patients. The dihydropyrimidine dehydrogenase gene (DPYD) was isolated, and its physical map and exon–intron organization were determined by analysis of P1, PAC, BAC, and YAC clones. TheDPYDgene was found to contain 23 exons ranging in size from 69 bp (exon 15) to 961 bp (exon 23). A physical map derived from a YAC clone indicated thatDPYDis at least 950 kb in length with 3 kb of coding sequence and an average intron size of about 43 kb.The previously reported 5′ donor splice site mutation present in pediatric thymine-uraciluria and cancer patients can now be assigned to exon 14. All 23 exons were sequenced from a series of human DNA samples, and three point mutations were identified in three racial groups as G1601A (exon 13, Ser534Asn), A1627G (exon 13, Ile543Val), and G2194A (exon 18, Val732Ile). These studies, which have established that theDPYDgene is unusually large, lay a framework for uncovering new mutations that are responsible for thymine-uraciluria and toxicity to fluoropyrimidine drugs.

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      Remarkably, DPD enzyme activity is subject to a wide variability, resulting in a possible range of enzymatic deficiencies that span from partial to complete loss of enzyme activity, with approximately 3%–5% of the entire population demonstrating partial deficiency and 0.2%–0.3% demonstrating complete deficiency (Fig. 2) [6,7]. DPD deficiency is partly linked to a genetic polymorphism since about 50% of patients who experienced early highly toxic and sometimes lethal effects were genotypically heterozygous or homozygous for known mutant alleles of the DPYD gene (Table 2) [8–11]. More than 30 variant DPD alleles have been published, and about half of them were considered to have potentially deleterious impact on DPD enzyme activity [12,13].

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    1

    Contributed equally to this work.

    2

    Present address: Center for Drug Evaluation and Research, Food and Drug Administration, Parklawn Building, Rockville, MD 20857.

    3

    Present address: Laboratorio de Bioquimica y Biologia Molecular, Facultad de Ciencias, Universidad de Extremadura, 06080-Badajoz, Spain.

    4

    To whom correspondence should be addressed at Laboratory of Metabolism, National Cancer Institute, Building 37, Room 3E-24, Bethesda, MD, 20892. Telephone: (301) 496-9067. Fax: (301) 496-8419. E-mail:[email protected].

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