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A novel mutation in the deoxyguanosine kinase gene causing depletion of mitochondrial DNA.
Jan-Willem Taanman, Ihab Kateeb, Ania C Muntau, Michaela Jaksch, Nadine Cohen, Hanna Mandel,
Recently, a homozygous single-nucleotide deletion in exon 2 of the deoxyguanosine kinase gene (DGUOK) was identified as the disease-causing mutation in 3 apparently unrelated Israeli-Druze families with depleted hepatocerebral mitochondrial DNA. We have discovered a novel homozygous nonsense mutation in exon 3 of DGUOK (313C-->T) from a patient born to nonconsanguineous German parents. This finding shows that mutations in DGUOK causing mitochondrial DNA depletion are not confined to a single ethnic group.
Annals of neurology - Aug 2002
The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.
H Mandel, R Szargel, V Labay, O Elpeleg, A Saada, A Shalata, Y Anbinder, D Berkowitz, C Hartman, M Barak, S Eriksson, N Cohen,
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.
Nature genetics - Nov 2001
Novel mutation in DGUOK in hepatocerebral mitochondrial DNA depletion syndrome associated with cystathioninuria.
Venu T Tadiboyina, Anthony Rupar, Paul Atkison, Annette Feigenbaum, Jonathan Kronick, Jian Wang, Robert A Hegele,
Mitochondrial depletion syndrome (MDS) refers to a heterogeneous group of mitochondrial disorders characterized by a reduction of the mtDNA copy number in affected tissues. Mutations in DGUOK encoding deoxyguanosine kinase (MIM 601465) cause the hepatocerebral form of MDS (MIM 251880). Cystathioninuria (MIM 219500) can result from mutations in CTH encoding cystathionine gamma lyase (MIM 607657) or can be a secondary finding in several diverse clinical conditions. We present three patients from two apparently unrelated old colony Mennonite families, each of whom had the hepatocerebral form of MDS together with cystathioninuria. Each affected child was homozygous for the novel DGUOK p.D255Y mutation, but had no CTH mutation, indicating that the hepatocerebral form of MDS might be associated with secondary cystathioninuria.
American journal of medical genetics. Part A - Jun 2005
Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations.
Peter Freisinger, Nancy Fütterer, Erwin Lankes, Klaus Gempel, Thomas M Berger, Johannes Spalinger, Alexandra Hoerbe, Claudia Schwantes, Martin Lindner, René Santer, Martin Burdelski, Hansjörg Schaefer, Bernhard Setzer, Ulrich A Walker, Rita Horváth,
Autosomal recessive mutations in deoxyguanosine kinase (DGUOK) have been identified in the hepatocerebral form of mitochondrial DNA (mtDNA) depletion syndrome.
Archives of neurology - Aug 2006
Mitochondrial DNA depletion and dGK gene mutations.
Leonardo Salviati, Sabrina Sacconi, Michelangelo Mancuso, David Otaegui, Pilar Camaño, Alberto Marina, Simon Rabinowitz, Rebecca Shiffman, Karen Thompson, Claire M Wilson, Annette Feigenbaum, Ali B Naini, Michio Hirano, Eduardo Bonilla, Salvatore DiMauro, Tuan H Vu,
Mitochondrial DNA depletion syndrome is a clinically heterogeneous group of disorders characterized by a reduction in mitochondrial DNA copy number. The recent discovery of mutations in the deoxyguanosine kinase (dGK) gene in patients with the hepatocerebral form of mitochondrial DNA depletion syndrome prompted us to screen 21 patients to determine the frequency of dGK mutations, further characterize the clinical spectrum, and correlate genotypes with phenotypes. We detected mutations in three patients (14%). One patient had a homozygous GATT duplication (nucleotides 763-766), and another had a homozygous GT deletion (nucleotides 609-610); both mutations lead to truncated proteins. The third patient was a compound heterozygote for two missense mutations (R142K and E227K) that affect critical residues of the protein. These mutations were associated with variable phenotypes, and their low frequencies suggests that dGK is not the only gene responsible for mitochondrial DNA depletion in liver. The patient with the missense mutations had isolated liver failure and responded well to liver transplantation, which may be a therapeutic option in selected cases.
Annals of neurology - Sep 2002