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

Mitochondrial DNA (mtDNA)-depletion syndromes (MDS; OMIM 251880) are phenot ypically heterogeneous, autosomal-recessive disorders characterized by tiss ue-specific reduction in mtDNA copy number(1-8). Affected individuals with the hepatocerebral form of MDS have early progressive liver failure and neu rological abnormalities, hypoglycemia and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respira tory chain complexes (I, III, IV, V) and mtDNA depletion(1-4,8-13). We used homozygosity mapping in three kindreds of Druze origin to map the gene cau sing hepatocerebral MDS to a region of 6.1 cM on chromosome 2p13, between m arkers D2S291 and D2S2116. This interval encompasses the gene (DGUOK) encod ing the mitochondrial deoxyguanosine kinase (dGK)(14-16). We identified a s ingle-nucleotide deletion (204delA) within the coding region of DGUOK that segregates with the disease in the three kindreds studied. Western-blot ana lysis 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)(17-19). T he association of mtDNA depletion with mutated DGUOK suggests that the salv age-pathway enzymes are involved in the maintenance of balanced mitochondri al dNTP pools.