The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet
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.
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- "These depletion syndromes are characterized by tissue-specific reduction of mtDNA copy number, which may result in serious organ failure (Spinazzola et al., 2006). Recessive defects in at least twelve nuclear genes TYMP, POLG1, POLG2, PEO1 (Twinkle), SLC25A4, DGUOK, TK2, SUCLA2, MPV17, SUCLG1, OPA1 and RRM2B have been associated with the MDSs (Nishino et al., 1999; Mandel et al., 2001; Saada et al., 2001; Van Goethem et al., 2001; Elpeleg et al., 2005; Spinazzola et al., 2006; Bourdon et al., 2007; Hakonen et al., 2007; Sarzi et al., 2007; Uusimaa et al., 2013). Clinically "
ABSTRACT: Mitochondrial DNA depletion syndromes (MDS) are often serious autosomal recessively inherited disorders characterized by tissue-specific mtDNA copy number reduction. Many genes, including MPV17, are associated with the hepatocerebral form of MDS. MPV17 encodes for a mitochondrial inner membrane protein with a poorly characterized function. Several MPV17 mutations have been reported in association with a heterogeneous group of early-onset manifestations, including liver disease and neurological problems. Mpv17-deficient mice present renal and hearing defects. We describe here a MPV17 truncation mutation in dogs. We found a 1-bp insertion in exon 4 of the MPV17 gene, resulting in a frameshift and early truncation of the encoded protein. The mutation halves MPV17 expression in the lymphocytes of the homozygous dogs and the truncated protein is not translated in transfected cells. The insertion mutation is recurrent and exists in many unrelated breeds, although is highly enriched in the Boxer breed. Unexpectedly, despite the truncation of MPV17, we could not find any common phenotypes in the genetically affected dogs. The lack of observable phenotype could be due to a late onset, mild symptoms or potential tissue-specific compensatory mechanisms. This study suggests species-specific differences in the manifestation of the MPV17 defects and establishes a novel large animal model to further study MPV17 function and role in mitochondrial biology.Biology Open 09/2015; DOI:10.1242/bio.013870 · 2.42 Impact Factor
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- "Both patients harboured recessive DGUOK mutations that had been previously reported in earlyonset mitochondrial disease patients with mtDNA depletion . DGUOK mutations remain associated in early-onset mitochondrial disease causing hepatocerebral mitochondrial depletion  and a very rare cause of late-onset PEO. "
ABSTRACT: Background: Progressive external ophthalmoplegia (PEO) is an eye movement disorder characterised by paresis of the extra ocular muscles and muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Classification of patients is particularly difficult due to overlapping phenotypes and a poor genotype-phenotype relationship. Despite the identification of several nuclear encoded genes causing PEO, over half of patients with clinically confirmed PEO do not have a genetic diagnosis. Objective: To systematically review genotypic and phenotypic correlates of published cases of adult-onset PEO. Methods: Patients were identified from interrogation of articles from Scopus, Medline via PubMed, and Genetic Abstracts databases using electronic searches (1st January 1970 to 8th November 2013). Reference lists and UniProt entries were also manually checked for additional articles. Results: Twelve nuclear encoded genes were identified (TYMP, SLC25A4, POLG, C10ORF2, OPA1, POLG2, RRM2B, TK2, DGUOK, MPV17, MGME1, and DNA2) systematically from 583 patients. At the time of writing, mutations in SPG7 and AFG3L2 genes were reported to be associated with ophthalmoparesis and multiple mtDNA deletions in fourteen additional adult-onset PEO patients, bringing the total number of known genes to fourteen. Conclusions: Diagnostic yield is still critically dependent on the meticulous clinical and biochemical characterisation of patients. Understanding the intimate relationship between genotype and phenotype remains a fundamental challenge. The results of this systematic review provide guidance to both patients and clinician about future prognosis, and will serve, in future, to assess methods of disease prevention and evaluation of targeted therapeutic strategies.
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- "Mitochondrial DNA depletion syndrome (MDS) is a frequent cause of severe childhood encephalomyopathy characterized molecularly by reduction of mtDNA copy number in tissues and insufficient synthesis of mitochondrial RC complexes (Hirano et al, 2001; Spinazzola & Zeviani, 2009). Mutations in eight nuclear genes have been identified as causes of infantile MDS (TK2, DGUOK, POLG, MPV17, RRM2B, SUCLA2, SUCLG1, and C10orf2) (Mandel et al, 2001; Saada et al, 2003; Naviaux & Nguyen, 2004; Elpeleg et al, 2005; Spinazzola et al, 2006; Bourdon et al, 2007; Ostergaard et al, 2007; Sarzi et al, 2007); 7 of the genes encode proteins involved in mtDNA replication or in the metabolism of deoxynucleotide triphosphate pools utilized as precursors for DNA replication (Copeland, 2012). Treatment for MDS, like most mitochondrial disorders, has been limited to supportive therapies; however, understanding the pathomechanism of MDS enables the design of treatment strategies targeting either the cause of the disease or the downstream metabolic defects. "
ABSTRACT: Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2−/−) knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13-day-old Tk2−/− mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2−/−200dCMP/dTMP) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency. Subject Categories Genetics, Gene Therapy & Genetic Disease; MetabolismEMBO Molecular Medicine 06/2014; 6(8). DOI:10.15252/emmm.201404092 · 8.67 Impact Factor