DPYD – Dihydropyrimidine Dehydrogenase Deficiency

Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD, catalyses the rate-limiting step of uracil and thymine catabolism. Biallelic loss-of-function variants in DPYD cause autosomal recessive DPD deficiency, characterised by thymine-uraciluria, global developmental delay, seizures and hypotonia, and confer high risk for severe or lethal fluoropyrimidine toxicity (PMID:2109146).

Genetic evidence includes over 30 patients with complete enzyme deficiency presenting at birth or in infancy (PMID:16151913) and a series of 22 patients across 17 unrelated families, all segregating biallelic DPYD variants (PMID:10071185). Two unrelated Dutch probands were homozygous for the invariant splice-site mutation c.1905+1G>A, demonstrating recurrence and population heterogeneity (PMID:8892022).

The DPYD variant spectrum comprises >52 alleles, including splice-site (c.1905+1G>A), frameshift (c.1898del), missense (c.85T>C (p.Cys29Arg)), deep intronic, exon-deleting and large intragenic rearrangements. The c.1905+1G>A splice mutation, which abolishes exon 14 and abrogates enzyme activity, accounts for >50% of alleles in complete-deficiency patients (PMID:8698850; PMID:8892022).

Functional studies confirm that splice-site and key missense mutations lead to near-complete loss of DPD activity. Exon-skipping due to c.1905+1G>A was shown by mRNA analysis, and expression of Cys29Arg and Arg235Trp in Escherichia coli produced inactive enzyme (PMID:8698850; PMID:9439663). Structural modelling further supports disruption of cofactor binding by variants such as p.Ala551Thr.

Incomplete genotype–phenotype correlation has been documented: asymptomatic homozygotes for c.1905+1G>A and variable expressivity within pedigrees indicate modifying factors or epistatic effects (PMID:9170156). This underscores the need for combined enzymatic and genetic screening.

Integration of genetic and experimental data establishes a definitive gene–disease relationship. Routine DPYD genotyping (including c.1905+1G>A) and phenotyping are essential for diagnosis and for guiding fluoropyrimidine dosing to prevent severe toxicity. Key take-home: comprehensive DPYD analysis enables accurate diagnosis of DPD deficiency and informs safe fluoropyrimidine therapy.

References

• Journal of inherited metabolic disease • 1990 • A new case of dihydropyrimidine dehydrogenase deficiency. PMID:2109146
• Journal of inherited metabolic disease • 2005 • Dihydropyrimidine dehydrogenase deficiency presenting at birth. PMID:16151913
• Human genetics • 1999 • Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. PMID:10071185
• Journal of inherited metabolic disease • 1996 • A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency. PMID:8892022
• The Journal of clinical investigation • 1996 • Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. PMID:8698850
• Human genetics • 1997 • Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. PMID:9439663
• Pharmacogenetics • 1997 • Lack of correlation between phenotype and genotype for the polymorphically expressed dihydropyrimidine dehydrogenase in a family of Pakistani origin. PMID:9170156

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