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The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA

A Correction to this article was published on 01 December 2001

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.

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Figure 1
Figure 2: Haplotypes of key affected individuals from the three kindreds.
Figure 3: DNA sequence electrophoregrams of the mutation in the Druze kindreds 1, 2 and 3.
Figure 4: Western-blot analysis of liver homogenate.

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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.

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Correspondence to Nadine Cohen.

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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

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