title: The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.
abstract: Mitochondrial DNA (mtDNA)-depletion syndromes (MDS; OMIM 251880) are phenotypically heterogeneous, autosomal-recessive disorders characterized by tissue-specific reduction in mtDNA copy number. 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 depletion. 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). 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). The association of mtDNA depletion with mutated DGUOK suggests that the salvage-pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools.
authors.affiliation: Metabolic Disease Unit, Department of Pediatrics, Rambam Medical Center, Technion-Israel Institute of Technology, Bruce Rappaport Faculty of Medicine, Haifa, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Mandel
authors.forename: R
authors.initials: R
authors.lastname: Szargel
authors.forename: V
authors.initials: V
authors.lastname: Labay
authors.forename: O
authors.initials: O
authors.lastname: Elpeleg
authors.forename: A
authors.initials: A
authors.lastname: Saada
authors.forename: A
authors.initials: A
authors.lastname: Shalata
authors.forename: Y
authors.initials: Y
authors.lastname: Anbinder
authors.forename: D
authors.initials: D
authors.lastname: Berkowitz
authors.forename: C
authors.initials: C
authors.lastname: Hartman
authors.forename: M
authors.initials: M
authors.lastname: Barak
authors.forename: S
authors.initials: S
authors.lastname: Eriksson
authors.forename: N
authors.initials: N
authors.lastname: Cohen
mesh_terms: D001483:Base Sequence; D015139:Blotting, Southern; D015153:Blotting, Western; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D016415:Sequence Alignment; D013687:Telencephalon / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase