Abstract
Mitochondrial DNA (mtDNA)–depletion syndromes (MDS; OMIM 251880) are phenotypically heterogeneous, autosomal-recessive disorders characterized by tissue-specific reduction in mtDNA copy number1,2,3,4,5,6,7,8. Affected individuals with the hepatocerebral form of MDS have early progressive liver failure and neurological abnormalities, hypoglycemia and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, V) and mtDNA depletion1,2,3,4,8,9,10,11,12,13. We used homozygosity mapping in three kindreds of Druze origin to map the gene causing hepatocerebral MDS to a region of 6.1 cM on chromosome 2p13, between markers D2S291 and D2S2116. This interval encompasses the gene (DGUOK) encoding the mitochondrial deoxyguanosine kinase (dGK)14,15,16. We identified a single-nucleotide deletion (204delA) within the coding region of DGUOK that segregates with the disease in the three kindreds studied. Western-blot analysis did not detect dGK protein in the liver of affected individuals. The main supply of deoxyribonucleotides (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by dGK and thymidine kinase-2 (TK2)17,18,19. The association of mtDNA depletion with mutated DGUOK suggests that the salvage-pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Moraes, C.T. et al. mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am. J. Hum. Genet. 48, 492–501 (1991).
Bodnar, A.G., Cooper, J.M., Holt, I.J., Leonard, J.V. & Schapira, A.H. Nuclear complementation restores mtDNA levels in cultured cells from a patient with mtDNA depletion. Am. J. Hum. Genet. 53, 663–669 (1993).
Spelbrink, J.N. et al. Familial mitochondrial DNA depletion in liver: haplotype analysis of candidate genes. Hum. Genet. 102, 327–331 (1998).
Taanman, J.W. et al. Molecular mechanisms in mitochondrial DNA depletion syndrome. Hum. Mol. Genet. 6, 935–942 (1997).
Marine-Garcia, J. & Goldenthal, M.J. Mitochondrial biogenesis defects and neuromuscular disorders. Pediatr. Neurol. 22, 122–129 (2000).
Marrioti, C. et al. Early-onset encephalomyopathy associated with tissue-specific mitochondrial DNA depletion: a morphological, biochemical and molecular-genetic study. J. Neurol. 242, 547–556 (1995).
Vu, T.H. et al. Clinical manifestations of mitochondrial DNA depletion. Neurology 50, 1783–1790 (1998).
Hirano, M. & Vu, T.H. Defects of intergenomic communication: where do we stand? Brain Pathol. 10, 451–461 (2000).
Mazziotta, M.R. et al. Fatal infantile liver failure associated with mitochondrial DNA depletion. J. Pediatr. 121, 896–901 (1992).
Maaswinkel-Mooij, P.D. et al. Depletion of mitochondrial DNA in the liver of a patient with lactic acidemia and hypoketotic hypoglycemia. J. Pediatr. 128, 679–683 (1996).
Bakker, H.D. et al. Depletion of mitochondrial deoxyribonucleic acid in a family with fatal neonatal liver disease. J. Pediatr. 128, 683–687 (1996).
Morris, A.A. Liver failure associated with mitochondrial DNA depletion. J. Hepatol. 28, 556–563 (1998).
Ducluzeau, P.H. et al. Depletion of mitochondria DNA associated with infantile cholestasis and progressive liver fibrosis. J. Hepatol. 30, 149–155 (1999).
Johansson, M., Bajalica-Lagercrantz, J. & Karlsson, A. Localization of the human deoxyguanosine kinase gene (DGUOK) to chromosome 2p13. Genomics 38, 450–451 (1996).
Wang, L., Hellman, U. & Eriksson, S. Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA. FEBS. Lett. 390, 39–43 (1996).
Johansson, M. & Karlsson, A. Cloning and expression of human doexyguanosine kinase cDNA. Proc. Natl Acad. Sci. USA. 93, 7258–7262 (1996).
Arner, E.S.J. & Eriksson, S. Mammalian deoxyribonucleoside kinases. Pharmacol. Ther. 67, 155–186 (1995).
Jullig, M. & Eriksson, S. Mitochondrial and submitochondrial localiztion of human deoxyguanosine kinase. Eur. J. Biochem. 267, 5466–5472 (2000).
Wang, L. et al. Human thymidine kinase 2: molecular cloning and characterization of the enzyme activity with antiviral and cytostatic nucleoside substrates. FEBS Lett. 443, 170–174 (1999).
Nishino, I., Spinazzola, A. & Hirano, M. Thymidine phosphrylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283, 689–692 (1999).
Nishino, I., Spinazzola, A. & Hirano M. MNGIE: from nuclear DNA to mitochondrial DNA. Neuromuscul. Disord. 11, 7–10 (2001).
Jenuth, J.P. & Mably, E.R & Snyder, F.F. Modelling of purine nucleoside metabolism during mouse embryonic development: relative routes of adenosine, deoxyadenosie, and deoxyguanosine metabolism. Biochem. Cell Biol. 74, 219–225 (1996).
Arnaudo, E. et al. Depletion of mitochondrial DNA in AIDS in patients with zidovudine-induced myopathy. Lancet 351, 508–510 (1991).
Lewis, W. & Dalakas, M.C. Mitochondrial toxicity of antiviral drugs. Nature Med. 1, 417–422 (1995).
Giblett, E.R. Immune cell function and recycling of purines. N. Engl. J. Med. 295, 1375–1376 (1976).
Saada, A. et al. Mitochondrial thymidine kinase mutations in mitochondrial DNA depletion myopathy. Nature Genet. 29, 342–344 (2001).
Rustin, P. et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chem. Acta 228, 35–51 (1994).
Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).
Gyapay, G., Ginot, F., Nguyen, S., Vignal, A. & Weissenbach, J. Genotyping procedures in linkage mapping. Methods 9, 91–97 (1996).
Cottingham, R.W. Jr, Idury, R.W. & Schafer, A.A. Faster sequential genetic linkage computation. Am. J. Hum. Genet. 53, 252–253 (1993).
Shaag, A. et al. Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews. Am. J. Med. Genet. 82, 177–182 (1999).
Acknowledgements
We gratefully acknowledge the collaboration of the affected families. This work was supported in part by the Joseph Elias Fund/Technion VPR fund (grant no. 181-421; to H.M.) and by the Swedish Medical Research council (to S.E.). V.L. is a recipient of a post-doctoral fellowship from the Juvenile Diabetes Foundation International.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Rights and permissions
About this article
Cite this article
Mandel, H., Szargel, R., Labay, V. et al. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29, 337–341 (2001). https://doi.org/10.1038/ng746
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng746
This article is cited by
-
Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome
Journal of Neurology (2021)
-
Stable retention of chloramphenicol-resistant mtDNA to rescue metabolically impaired cells
Scientific Reports (2020)
-
Whole exome sequencing reveals two novel compound heterozygous mutations in TWNK as a cause of the hepatocerebral form of mitochondrial DNA depletion syndrome: a case report
BMC Medical Genetics (2019)
-
Clinical and molecular characterization of three patients with Hepatocerebral form of mitochondrial DNA depletion syndrome: a case series
BMC Medical Genetics (2019)
-
POLG-related disorders and their neurological manifestations
Nature Reviews Neurology (2019)