Alternative titles; symbols
HGNC Approved Gene Symbol: DGUOK
SNOMEDCT: 783734000;
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38): 2:73,926,880-73,958,946 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.1 | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | 251880 | Autosomal recessive | 3 |
| Portal hypertension, noncirrhotic, 1 | 617068 | Autosomal recessive | 3 | |
| Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 | 617070 | Autosomal recessive | 3 |
Purine deoxyribonucleoside analogs are extensively used in treatment of lymphoproliferative disorders. These compounds are administered as pro-drugs, and their efficiency is dependent on intracellular phosphorylation to the corresponding triphosphates. In mammalian cells, the phosphorylation of purine deoxyribonucleosides is mediated predominantly by 2 deoxyribonucleoside kinases: cytosolic deoxycytidine kinase (DCK; EC 2.7.1.74; 125450) and mitochondrial deoxyguanosine kinase (DGK; EC 2.7.1.113).
Johansson and Karlsson (1996) used the human DCK cDNA sequence to find homologous cDNA sequences in an attempt to identify novel DCK-related enzymes. Several cDNA clones with 40 to 50% DNA sequence identity to human DCK were found in the GenBank sequence database, and the cDNA with the longest open reading frame was expressed in Escherichia coli. The protein was found to have the same substrate specificity as purified native DGK. Furthermore, the N-terminal sequence contained a possible mitochondrial translocation signal. Johansson and Karlsson (1996) suggested that DCK may be present only in the cytosol and DGK only in mitochondria. The presumed mitochondrial translocation signal would be removed by cleavage at a putative mitochondrial peptidase cleavage site to give a mature protein size of 28 kD. Northern blot analysis detected a 1.3-kb DGK transcript with no cross-hybridization to the 2.8-kb DCK mRNA. DGK mRNA was detected in all tissues investigated with the highest expression levels in muscle, brain, liver, and lymphoid tissues.
Mitochondrial DNA Depletion Syndrome 3 (Hepatocerebral Type)
Mandel et al. (2001) used homozygosity mapping in 3 kindreds of Druze origin to map a hepatocerebral type of mitochondrial DNA depletion syndrome (MTDPS3; 251880) to a region of 6.1 cM on chromosome 2p13. This interval encompasses the DGUOK gene. They identified a 1-bp deletion (601465.0001) within the DGUOK gene that segregated with the disease in the 3 kindreds studied. Affected individuals had early onset of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, and V) and mtDNA depletion. Western blot analysis failed to detect DGK protein in the liver of affected persons. The main supply of deoxyribonucleotides (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by DGK and thymidine kinase-2 (TK2; 188250). The association of mtDNA depletion with mutated DGUOK suggested that the salvage pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools.
Taanman et al. (2003) studied fibroblasts from a patient described by Taanman et al. (2002) who was homozygous for an arg105-to-ter substitution in the DGUOK gene (R105X; 601465.0002). Although mtDNA synthesis was cell cycle-independent in control fibroblasts, mtDNA synthesis occurred mainly during the S-phase in deoxyguanosine kinase-deficient cells. Consistent with this observation, the mtDNA content of exponentially growing, deoxyguanosine kinase-deficient cells was only mildly affected. When cycling was inhibited by serum deprivation and cells were in a resting state, however, the mtDNA content dropped considerably in deoxyguanosine kinase-deficient cells, yet remained stable in control fibroblasts. The decline in mtDNA content in resting, deoxyguanosine kinase-deficient cells could be prevented by deoxyguanosine monophosphate (DGMP) and deoxyadenosine monophosphate (dAMP) supplementation, providing conclusive evidence that substrate limitation triggers mtDNA depletion in deoxyguanosine kinase-deficient cells.
Tadiboyina et al. (2005) reported 3 patients with the hepatocerebral form of mtDNA depletion syndrome associated with cystathioninuria. All 3 children were homozygous for a mutation in the DGUOK gene (D255Y; 601465.0007), but had no mutations in the cystathionine gamma-lyase gene (CTH; 607657), indicating that the hepatocerebral form of mtDNA depletion syndrome might be associated with secondary cystathioninuria.
Autosomal Recessive Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions 4
In 6 patients, including 2 sibs, with adult-onset autosomal recessive progressive external ophthalmoplegia-4 (PEOB4; 617070), Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene (601465.0008; 601465.0010-601465.0015). One of the patients also had features of MTDPS3. The mutations, which were found by targeted exome sequencing and confirmed by standard sequencing, included both missense and truncating mutations. Skeletal muscle from patients showed mtDNA deletions as well as decreased protein levels and activity of DGUOK. The findings expanded the phenotype associated with DGUOK mutations. In this study, DGUOK mutations accounted for 5.6% of 90 probands with mtDNA deletions in skeletal muscle.
Noncirrhotic Portal Hypertension 1
In 3 patients from 2 unrelated consanguineous Turkish families with noncirrhotic portal hypertension-1 (NCPH1; 617068), Vilarinho et al. (2016) identified a homozygous missense mutation in the DGUOK gene (N46S; 601465.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families.
Zhou et al. (2019) found that Dguok -/- mice appeared normal at birth but began to lose weight at week 6, with decreased adipose tissue and significantly higher relative weights of liver, kidney, and heart at week 8. Fur color changed from black to blueish gray beginning at week 16, with completion at week 20. Liver, brain, heart, and skeletal muscle of Dguok -/- mice showed mitochondrial DNA (mtDNA) deficiency, with liver most severely affected. Liver mitochondrial ultrastructure was abnormal, with decreased expression of mtDNA-encoded CoxI (MTCO1; 516030) and Nd1 (MTND1; 516000). Mitochondrial dysfunction led to liver damage, decreased subcutaneous fat, and accumulation of lipofuscin in liver tissue with increased oxidative stress. Microarray analysis of liver tissue revealed increased catabolic lipid metabolism and upregulation of the de novo dNTP pathway in Dguok -/- mice.
In affected members of 3 unrelated Israeli-Druze families with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880), manifest with hepatic and cerebral involvement, Mandel et al. (2001) identified a homozygous 1-bp deletion (204delA) in the DGUOK gene, predicted to result in a frameshift and premature termination at codon 80. All parents carried the mutation, and unaffected sibs were either carriers or homozygous with respect to the wildtype allele. There were 19 affected members in the 3 kindreds. Death usually occurred before 1 year of age. Enzymatic activities of the mitochondrial respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, and IV) were reduced to various extents, whereas complex II enzymatic activity, which is encoded solely by nuclear genes, was normal. Muscle tissue from 7 affected patients showed normal histology and respiratory chain complex activities.
In 2 German brothers with mitochondrial DNA-depletion syndrome-3 (MTDPS3; 251880) characterized by lactic acidosis, hepatomegaly, hypoglycemia, jaundice, and encephalopathy with hypotonia, hyperreflexia, and nystagmus, Taanman et al. (2002) identified a homozygous 313C-T transition in exon 3 of the DGUOK gene, resulting in an arg105-to-ter (R105X) substitution, and a 173-amino acid truncation at the C terminus of the protein product. The unaffected parents were heterozygous for the mutation.
In a patient with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880), Salviati et al. (2002) identified a homozygous 4-bp duplication (GATT) at nucleotide 763 in the DGUOK gene, resulting in a frameshift and premature termination of the protein. The patient presented at 2 months of age with poor feeding, hypotonia, nystagmus, metabolic acidosis, hepatomegaly, and elevated liver enzymes. She died at 5 months of age. Both parents and an unaffected sister were heterozygous for the mutation.
In a patient with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement, Salviati et al. (2002) identified a homozygous 2-bp deletion (609delGT) in the DGUOK gene, resulting in a premature stop codon and a truncated protein. He presented with jaundice and hepatomegaly and died at 6 months of age.
In a patient with the hepatocerebral type of mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880), Salviati et al. (2002) identified compound heterozygosity for mutations in the DGUOK gene: a 425G-A transition resulting in an arg142-to-lys (R142K) substitution in a conserved area of the protein, likely affecting the enzyme's active site, and a 679G-A transition (601465.0006) resulting in a glu227-to-lys (E227K) substitution in a conserved area of the protein, likely resulting in impaired folding of the protein. DGUOK activity was decreased, but not absent, in the patient's liver, indicating that the point mutations do not inactivate the enzyme to the same extent as truncating mutations. The patient underwent successful liver transplantation.
For discussion of the glu227-to-lys (E227K) mutation in the DGUOK gene that was found in compound heterozygous state in a patient with hepatocerebral-type mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) by Salviati et al. (2002), see 601465.0005.
In 3 patients from 2 apparently unrelated Old Colony Mennonite families, each of whom had the hepatocerebral type of mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) associated with cystathioninuria, Tadiboyina et al. (2005) identified homozygosity for a G-to-T transversion in the first nucleotide position of codon 255 in exon 6 of the DGUOK gene, resulting in an asp255-to-tyr (D255Y) substitution. All of the parents were unaffected and heterozygous for the mutation.
Mitochondrial DNA Depletion Syndrome 3
In a French boy with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement only (Ducluzeau et al., 2002), Mousson De Camaret et al. (2007) identified compound heterozygous missense mutations in the DGUOK gene: a c.137A-G transition (c.137A-G, NM_080916) in exon 1, resulting in an asn46-to-ser (N46S) substitution at a conserved residue in the P-loop domain, and a c.797T-G transversion in exon 6, resulting in a leu266-to-arg (L266R; 601465.0009) substitution in the C-terminal alpha-9 helix domain. The patient had a very unusual disease course: he presented in infancy with severe liver disease, but then had spontaneous improvement beginning at about 32 months of age. He showed normal development by 4 years of age and ultimately had almost complete reversal of the phenotype; he never had neurologic involvement. In vitro studies by Mousson De Camaret et al. (2007) showed that these mutations retained 10 to 14% residual enzymatic activity, which likely contributed to the unusual phenotypic reversal in this patient.
Sarzi et al. (2007) identified a homozygous N46S mutation in a patient (patient 9) with MTDPS3 who developed progressive liver disease at 2 months of age and had liver failure with cirrhosis at age 10 months.
Autosomal Recessive Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions 4
In a woman with features of MTDPS3, Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene: N46S and a 2-bp deletion in exon 5 (c.605_606delGA; 601465.0011), resulting in a frameshift and premature termination (Arg202TyrfsTer12). She presented in infancy with liver failure and underwent successful liver transplant at age 9 months. She was clinically well until age 20 years, when she developed acute myopathic episodes associated with increased serum creatine kinase and rhabdomyolysis; this latter phenotype was consistent with autosomal recessive progressive external ophthalmoplegia-4 (PEOB4; 617070).
Noncirrhotic Portal Hypertension 1
In 3 patients from 2 unrelated consanguineous Turkish families with noncirrhotic portal hypertension-1 (NCPH1; 617068), Vilarinho et al. (2016) identified a homozygous N46S mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families, and was not found in the 1000 Genomes Project database or in 894 control Turkish exomes. It was found at a very low frequency (3.134 x 10(-5)) in the ExAC database, only in the heterozygous state. Haplotype analysis suggested a founder effect. The findings significantly expanded the phenotype associated with the N46S mutation.
For discussion of the c.797T-G transversion (c.797T-G, NM_080916) in exon 6 of the DGUOK gene, resulting in a leu266-to-arg (L266R) substitution, that was found in compound heterozygous state in a patient with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with only hepatic involvement by Mousson De Camaret et al. (2007), see 601465.0008.
In 2 unrelated women (patients 1 and 2) with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4; 617070), Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene. Both patients carried a c.462T-A transversion (c.462T-A, NM_080916.2) in exon 4, resulting in an asn154-to-lys (N154K) substitution at a highly conserved residue on 1 allele. One patient carried a 2-bp deletion in exon 5 (c.605_606delGA; 601465.0011), resulting in a frameshift and premature termination (Arg202TyrfsTer12), on the other allele, whereas the other patient carried a c.130G-A transition in exon 1, resulting in a glu44-to-lys (E44K; 601465.0012) substitution at a highly conserved residue, on the other allele. The N154K mutation was present at a low frequency in the Exome Variant Server database (0.04%) and the dbSNP database (0.002), but was not found in 226 control alleles. Both patients had decreased DGUOK protein levels and activity in skeletal muscle compared to controls. The E44K variant was not found in 226 control alleles.
For discussion of the 2-bp deletion (c.605_606delGA, NM_080916.2) in exon 5 of the DGUOK gene, resulting in a frameshift and premature termination (Arg202TyrfsTer12), that was found in compound heterozygous state in a patient with features of both mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) and autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4; 617070) by Ronchi et al. (2012), see 601465.0008.
For discussion of the c.130G-A transition (c.130G-A, NM_080916.2) in the DGUOK gene, resulting in a glu44-to-lys (E44K; 601465.0012) substitution, that was found in compound heterozygous state in a patient with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4; 617070), by Ronchi et al. (2012), see 601465.0010.
In 3 patients, including 2 sibs, (patients 3, 5.1, and 5.2) with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4; 617070), Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene. All 3 carried a heterozygous c.509A-G (c.509A-G, NM_080916.2) transition in exon 4, resulting in a gln170-to-arg (Q170R) substitution at a highly conserved residue. The Q107R variant was found at an allele frequency of 1.98% among a group of Italian controls, at a frequency of 1.6% in the Exome Variant Server database, and at a frequency of 0.029 in the dbSNP database. Functional studies of this variant were not performed, and the pathogenic significance was uncertain. Patient 3 carried a c.186C-A transversion in exon 2, resulting in a tyr62-to-ter (Y62X; 601465.0014) substitution in the other allele, whereas the sibs carried a C-to-G transversion in intron 3 (c.444-11C-G; 601465.0015) on the other allele, predicted to result in a splicing defect. Analysis of cells from patient 5.1 suggested that the splice site mutation resulted in nonsense-mediated mRNA decay. Analysis of skeletal muscle from 1 of the sibs showed decreased DGUOK protein and activity (70% reduction) to controls. Muscle samples were not available for study from patient 3.
For discussion of the c.186C-A transversion (c.186C-A, NM_080916.2) in exon 2 of the DGUOK gene, resulting in a tyr62-to-ter (Y62X) substitution, that was found in compound heterozygous state in a patient with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4; 617070) by Ronchi et al. (2012), see 601465.0013.
For discussion of the C-to-G transversion in intron 3 of the DGUOK gene (c.444-11C-G, NM_080916.2) resulting in a splicing defect and nonsense-mediated mRNA decay, that was found in compound heterozygous state in 2 sibs with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4; 617070) by Ronchi et al. (2012), see 601465.0013.
Ducluzeau, P.-H., Lachaux, A., Bouvier, R., Duborjal, H., Stepien, G., Bozon, D., Mousson de Camaret, B. Progressive reversion of clinical and molecular phenotype in a child with liver mitochondrial DNA depletion. J. Hepatol. 36: 698-703, 2002. [PubMed: 11983456] [Full Text: https://doi.org/10.1016/s0168-8278(02)00021-1]
Johansson, M., Karlsson, A. Cloning and expression of human deoxyguanosine kinase cDNA. Proc. Nat. Acad. Sci. 93: 7258-7262, 1996. [PubMed: 8692979] [Full Text: https://doi.org/10.1073/pnas.93.14.7258]
Mandel, H., Szargel, R., Labay, V., Elpeleg, O., Saada, A., Shalata, A., Anbinder, Y., Berkowitz, D., Hartman, C., Barak, M., Eriksson, S., Cohen, N. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nature Genet. 29: 337-341, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001. [PubMed: 11687800] [Full Text: https://doi.org/10.1038/ng746]
Mousson de Camaret, B., Taanman, J. W., Padet, S., Chassagne, M., Mayencon, M., Clerc-Renaud, P., Mandon, G., Zabot, M.-T., Lachaux, A., Bozon, D. Kinetic properties of mutant deoxyguanosine kinase in a case of reversible hepatic mtDNA depletion. Biochem. J. 402: 377-385, 2007. [PubMed: 17073823] [Full Text: https://doi.org/10.1042/BJ20060705]
Ronchi, D., Garone, C., Bordoni, A., Gutierrez Rios, P., Calvo, S. E., Ripolone, M., Ranieri, M., Rizzuti, M., Villa, L., Magri, F., Corti, S., Bresolin, N., Mootha, V. K., Moggio, M., DiMauro, S., Comi, G. P., Sciacco, M. Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. Brain 135: 3404-3415, 2012. [PubMed: 23043144] [Full Text: https://doi.org/10.1093/brain/aws258]
Salviati, L., Sacconi, S., Mancuso, M., Otaegui, D., Camano, P., Marina, A., Rabinowitz, S., Shiffman, R., Thompson, K., Wilson, C. M., Feigenbaum, A., Naini, A. B., Hirano, M., Bonilla, E., DiMauro, S., Vu, T. H. Mitochondrial DNA depletion and dGK gene mutations. Ann. Neurol. 52: 311-316, 2002. [PubMed: 12205643] [Full Text: https://doi.org/10.1002/ana.10284]
Sarzi, E., Bourdon, A., Chretien, D., Zarhrate, M., Corcos, J., Slama, A., Cormier-Daire, V., de Lonlay P., Munnich, A., Rotig, A. Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. J. Pediat. 150: 531-534, 2007. [PubMed: 17452231] [Full Text: https://doi.org/10.1016/j.jpeds.2007.01.044]
Taanman, J.-W., Kateeb, I., Muntau, A. C., Jaksch, M., Cohen, N., Mandel, H. A novel mutation in the deoxyguanosine kinase gene causing depletion of mitochondrial DNA. Ann. Neurol. 52: 237-239, 2002. [PubMed: 12210798] [Full Text: https://doi.org/10.1002/ana.10247]
Taanman, J.-W., Muddle, J. R., Muntau, A. C. Mitochondrial DNA depletion can be prevented by dGMP and dAMP supplementation in a resting culture of deoxyguanosine kinase-deficient fibroblasts. Hum. Molec. Genet. 12: 1839-1845, 2003. [PubMed: 12874104] [Full Text: https://doi.org/10.1093/hmg/ddg192]
Tadiboyina, V. T., Rupar, A., Atkison, P. Feigenbaum, A., Kronick, J., Wang, J., Hegele, R. A. Novel mutation in DGUOK in hepatocerebral mitochondrial DNA depletion syndrome associated with cystathioninuria. Am. J. Med. Genet. 135A: 289-291, 2005. [PubMed: 15887277] [Full Text: https://doi.org/10.1002/ajmg.a.30748]
Vilarinho, S., Sari, S., Yilmaz, G., Stiegler, A. L., Boggon, T. J., Jain, D., Akyol, G., Dalgic, B., Gunel, M., Lifton, R. P. Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension. Hepatology 63: 1977-1986, 2016. [PubMed: 26874653] [Full Text: https://doi.org/10.1002/hep.28499]
Zhou, X., Curbo, S., Zhao, Q., Krishnan, S., Kuiper, R., Karlsson, A. Severe mtDNA depletion and dependency on catabolic lipid metabolism in DGUOK knockout mice. Hum. Molec. Genet. 28: 2874-2884, 2019. [PubMed: 31127938] [Full Text: https://doi.org/10.1093/hmg/ddz103]