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DPYD
dihydropyrimidine dehydrogenase
The DPYD gene provides instructions for the dihydropyrimidine dehydrogenase enzyme, which is essential for the metabolism of pyrimidines like uracil and thymine. DPYD is a gene that codes for the dihydropyrimidine dehydrogenase enzyme.
DPYD is located on the short (p) arm of chromosome 1, at band 1p21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The DPYD gene, also known as dihydropyrimidine dehydrogenase, encodes an enzyme vital for the body's metabolic processes. This enzyme is primarily involved in breaking down pyrimidine molecules, specifically uracil and thymine, when they are no longer needed. The DPYD gene is particularly relevant in pharmacogenomics, as its function can influence how individuals metabolise certain medications.
What the gene does
The DPYD gene directs the production of dihydropyrimidine dehydrogenase, an enzyme that catalyses the initial step in the breakdown of pyrimidines. Pyrimidines such as uracil and thymine are fundamental building blocks of DNA and RNA. These nucleotides also play roles in energy-related molecules like ATP and GTP within cells. The enzyme converts uracil into 5,6-dihydrouracil, whilst thymine becomes 5,6-dihydrothymine through the same process. The resulting breakdown products are then either excreted from the body or recycled for other cellular functions. Proper functioning of this enzyme ensures efficient removal of excess pyrimidines, preventing their accumulation in tissues and body fluids.
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Chromosome location
The DPYD gene is located on the short arm of chromosome 1, specifically at position 1p21.3. This region of the genome contains various genes with diverse functions.
Protein structure
The dihydropyrimidine dehydrogenase protein is composed of 1025 amino acids. It features several important functional regions. These include three distinct 4Fe-4S ferredoxin-type domains. The first 4Fe-4S ferredoxin-type domain is found between amino acids 69 and 100. A second 4Fe-4S ferredoxin-type domain is located from amino acids 944 to 976, and a third 4Fe-4S ferredoxin-type domain is present between amino acids 978 and 1007. These domains are crucial for the protein's enzymatic activity.
Key variants
Variants within the DPYD gene can alter the function of the dihydropyrimidine dehydrogenase enzyme. These genetic changes can range from single nucleotide changes to larger deletions or insertions, impacting the enzyme's efficiency in breaking down pyrimidines. The specific effect of a variant depends on its location and the resulting alteration to the protein structure or production.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1109_1110del | p.Ile370fs | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.127_134del | p.Lys42_Arg43insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.1379dup | p.Leu461fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodevelopmental delay |
c.1681C>T | p.Arg561Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.1905+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.205G>T | p.Glu69Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.208C>T | p.Arg70Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.257C>T | p.Pro86Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.299_302del | p.Phe100fs | Pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
c.661G>T | p.Glu221Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dihydropyrimidine dehydrogenase deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Genetic variations in the DPYD gene are primarily associated with dihydropyrimidine dehydrogenase deficiency. This condition arises when DPYD gene mutations hinder the breakdown of uracil and thymine, leading to their accumulation in the body. Over 50 different mutations in the DPYD gene have been identified in individuals with this deficiency. These elevated levels of uracil and thymine can be detected in blood, urine, and the fluid that surrounds the brain. The DPYD gene is also relevant in pharmacogenomics due to its role in metabolising certain medications.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DPYD variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The DPYD gene is included in several NHS England Genomic Medicine Service national genomic test directories, as assessed by PanelApp. It has a 'green' status for panels related to Early onset or syndromic epilepsy, Inherited white matter disorders, Intellectual disability, Likely inborn error of metabolism (R98), Undiagnosed metabolic disorders, and White matter disorders and cerebral calcification - childhood onset, indicating that there is strong evidence for its clinical utility in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the DPYD gene?
The DPYD gene provides instructions for making the dihydropyrimidine dehydrogenase enzyme. This enzyme is crucial for the initial step in breaking down pyrimidine molecules, specifically uracil and thymine, in the body.
What is dihydropyrimidine dehydrogenase deficiency?
Dihydropyrimidine dehydrogenase deficiency is a condition caused by mutations in the DPYD gene. These mutations impair the enzyme's ability to break down uracil and thymine, leading to their build-up in the body's fluids.
How does DPYD relate to medication?
The DPYD gene is significant in pharmacogenomics because the enzyme it produces metabolises certain medications. Variations in DPYD can affect how an individual processes these drugs.
References
- Ciccolini J, Gross E, Dahan L. Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: hype or hope? Clinical colorectal cancer. 2010. PMID: 20920994
- van Kuilenburg AB, Meijer J, Mul AN. Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3). Human genetics. 2009. PMID: 19296131
- Saif MW, Mattison L, Carollo T. Dihydropyrimidine dehydrogenase deficiency in an Indian population. Cancer chemotherapy and pharmacology. 2006. PMID: 16421754
- Mattison LK, Fourie J, Desmond RA. Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006. PMID: 17000684
- Al-Sanna'a NA, Van Kuilenburg AB, Atrak TM. Dihydropyrimidine dehydrogenase deficiency presenting at birth. Journal of inherited metabolic disease. 2005. PMID: 16151913
- van Kuilenburg AB, De Abreu RA, van Gennip AH. Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Annals of clinical biochemistry. 2003. PMID: 12542909
- van Kuilenburg AB, Dobritzsch D, Meinsma R. Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. The Biochemical journal. 2002. PMID: 11988088
- Van Kuilenburg AB, Vreken P, Abeling NG. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Human genetics. 1999. PMID: 10071185