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DGUOK
deoxyguanosine kinase
The DGUOK gene provides instructions for an enzyme called deoxyguanosine kinase, which is vital for maintaining mitochondrial DNA and cellular energy production. The DGUOK gene encodes the mitochondrial enzyme deoxyguanosine kinase.
DGUOK is located on the short (p) arm of chromosome 2, at band 2p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The DGUOK gene provides the genetic blueprint for deoxyguanosine kinase, an enzyme located within the mitochondria, the cell's primary energy producers. This enzyme is essential for the healthy functioning of mitochondria, specifically by supporting the integrity of mitochondrial DNA (mtDNA).
Disruptions in DGUOK function, often due to genetic variants, are associated with a range of inherited disorders, including deoxyguanosine kinase deficiency. These conditions primarily affect organs with high energy demands, such as the liver, brain, and muscles.
What the gene does
The deoxyguanosine kinase enzyme, encoded by the DGUOK gene, is critically involved in the mitochondrial salvage pathway. This pathway recycles nucleosides, which are the fundamental building blocks of DNA. Specifically, deoxyguanosine kinase phosphorylates deoxyguanosine, converting it into a form that can be incorporated into mitochondrial DNA.
Mitochondrial DNA is distinct from nuclear DNA and is crucial for the production of proteins essential for oxidative phosphorylation, the main process of energy generation in the cell. By ensuring a steady supply of nucleoside precursors, DGUOK plays a vital role in the replication and repair of mtDNA, thereby maintaining normal mitochondrial function and cellular energy homeostasis.
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Chromosome location
The DGUOK gene is situated on chromosome 2, specifically at position 2p13.1. This location refers to the short arm (p) of chromosome 2, in region 1, band 3, sub-band 1.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the DGUOK gene can alter the structure and function of the deoxyguanosine kinase enzyme. Many identified variants involve changes to single amino acids, which are the protein's building blocks. Other types of variants can lead to the production of an abnormally short, non-functional protein. These genetic alterations can impair the enzyme's ability to maintain mitochondrial DNA.
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.155C>T | p.Ser52Phe | Pathogenic/Likely pathogenic | ★★☆☆ | DGUOK-related disorder |
c.195G>A | p.Trp65Ter | Pathogenic | ★★☆☆ | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 |
c.235C>T | p.Gln79Ter | Pathogenic | ★★☆☆ | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 |
c.352C>T | p.Arg118Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.443+1G>A | - | Pathogenic | ★★☆☆ | not provided |
c.444-62C>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) |
c.493G>A | p.Glu165Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) |
c.494A>T | p.Glu165Val | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) |
c.592-4_592-3del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) |
c.707+3_707+6del | - | Pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) |
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
Variants in the DGUOK gene are primarily associated with deoxyguanosine kinase deficiency, an inherited disorder. This condition can severely impact organs such as the liver, muscles, and brain due to impaired mitochondrial function. Another condition sometimes linked to DGUOK variants is progressive external ophthalmoplegia.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DGUOK variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The DGUOK gene is included in several expert-curated panels within the NHS Genomic Medicine Service's PanelApp. It has a 'green' status for conditions such as Acute rhabdomyolysis, Cholestasis, Mitochondrial disorders, and Mitochondrial liver disease, indicating strong evidence for its involvement in these conditions. It is also listed for Likely inborn error of metabolism and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the DGUOK gene?
The DGUOK gene provides instructions for the enzyme deoxyguanosine kinase, which is crucial for synthesising and maintaining mitochondrial DNA (mtDNA). This ensures the mitochondria, the cell's powerhouses, can function correctly.
What conditions are associated with variants in the DGUOK gene?
Variants in the DGUOK gene are primarily linked to deoxyguanosine kinase deficiency, an inherited disorder that can affect the liver, muscles, and brain due to mitochondrial dysfunction. It can also be associated with progressive external ophthalmoplegia.
How does the DGUOK gene affect mitochondrial DNA?
The DGUOK enzyme creates building blocks necessary for mitochondrial DNA (mtDNA) replication and repair. Without a functional DGUOK enzyme, mtDNA can become damaged or depleted, impairing the mitochondria's ability to produce energy for the cell.
References
- Brahimi N, Jambou M, Sarzi E. The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Molecular genetics and metabolism. 2009. PMID: 19394258
- Dimmock DP, Zhang Q, Dionisi-Vici C. Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. Human mutation. 2008. PMID: 18205204
- Freisinger P, Fütterer N, Lankes E. Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations. Archives of neurology. 2006. PMID: 16908739
- Mancuso M, Ferraris S, Pancrudo J. New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome. Archives of neurology. 2005. PMID: 15883261
- Slama A, Giurgea I, Debrey D. Deoxyguanosine kinase mutations and combined deficiencies of the mitochondrial respiratory chain in patients with hepatic involvement. Molecular genetics and metabolism. 2005. PMID: 16263314
- Saada-Reisch A. Deoxyribonucleoside kinases in mitochondrial DNA depletion. Nucleosides, nucleotides & nucleic acids. 2004. PMID: 15571232
- Wang L, Eriksson S. Mitochondrial deoxyguanosine kinase mutations and mitochondrial DNA depletion syndrome. FEBS letters. 2003. PMID: 14623087
- Salviati L, Sacconi S, Mancuso M. Mitochondrial DNA depletion and dGK gene mutations. Annals of neurology. 2002. PMID: 12205643
- Mandel H, Szargel R, Labay V. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nature genetics. 2001. PMID: 11687800
- Adam MP, Bick S, Mirzaa GM. Deoxyguanosine Kinase Deficiency. 1993. PMID: 20301766