The DGUOK gene is located chromosome on 2p13.1. It provides instruction for making a mitochondrial enzyme of 277 amino acids called deoxyguanosine kinase. This enzyme is involved in producing and maintaining the building blocks of mitochondrial DNA. Specifically, it is responsible for phosphorylation of purine deoxyribonucleosides in the mitochondrial matrix.
Defects in this enzyme are the cause of Mitochondrial DNA depletion syndrome 3 (MTDPS3), a disorder characterized by onset in infancy of progressive liver failure, hypoglycemia, increased lactate in body fluids, and neurologic abnormalities including hypotonia, encephalopathy, and peripheral neuropathy.
The DGUOK gene consists of seven coding exons, and spans approximately 32 kb in the genomic DNA. Mutations in this gene are associated with DNA depletion syndrome 3 (MTDPS3). In addition, about 40 different mutations in this gene have been identified in patients with deoxyguanosine kinase deficiency. Mutations in this gene result in an inactive deoxyguanosine kinase enzyme that cause a depletion in the mtDNA and impairs its function in many of the body's cells and tissues.
[See: Palestine > Mandel et al., 2001].
Mandel et al (2001) used three unrelated consanguineous Druze kindreds affected by hepatocerebral MDS to map the disease locus. Homozygosity mapping using 168 microsatellite markers identified a region of shared homozygosity at chromosome 2p13, with a maximum lod score of 6.7 at a 15.6 cM interval. Fine mapping narrowed this locus down to a 6.1 cM interval between markers D2S291 and D2S2116. The three kindreds showed a segment of shared haplotypes, suggesting the presence of a founder mutation. The DGUOK gene, located within this interval, was considered to be a candidate gene, and all seven exons of this gene were sequenced. The results showed a 1-nt deletion (204delA) in all affected patients. This mutation predicted a frame-shift with a premature truncation. All the parents were carriers, while the unaffected siblings were found to be either carriers or homozygous with the wild type allele. The mutation was not found in 100 ethically matched controls. In addition, in two other affected families, one of Druze and one of Moroccan origin, in which the disease showed linkage to the DGUOK gene, no mutation could be detected in the coding region of the gene. Mandel et al (2001) suggested that in these cases, the mutation may be confined to the non-coding region of the gene.
Al-Hussaini et al. (2014) studied 20 infants with suspected hepatocerebral mitochondrial DNA depletion syndrome referred to a tertiary care center between 2007 and 2013. They identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure encountered during the study period. Seven patients had mutations in the MPV17 gene (three novel mutations) while four patients had DGUOK mutations (of which two were novel mutations).