title: Deoxyguanosine kinase mutations and combined deficiencies of the mitochondrial respiratory chain in patients with hepatic involvement.
abstract: The activity of deoxyguanosine kinase (DGUOK), a mitochondrial enzyme involved in the anabolism of mitochondrial (mt) deoxyribonucleotides, governs the maintenance of the mtDNA. Deleterious mutations of the DGUOK gene are thus associated with mtDNA depletion and result in combined deficiencies of mtDNA-encoded respiratory chain enzymes. With the aim to estimate the prevalence of DGUOK mutations in a cohort of 30 patients with hepatocerebral disease and combined respiratory chain deficiencies, we studied the DGUOK gene and identified previously unreported mutations in five families. Two patients and their affected sibs, born to non-consanguineous parents, were homozygous for a missense mutation (M1T, and L250S, respectively). One patient presented a homozygous 4 pb insertion (796 insTGAT) and two other patients, and their affected sibs, were compound heterozygous (E165V/L266R and E211G/L266R, respectively). These findings allowed us to propose prenatal diagnosis in two families. In conclusion, we observed a high prevalence of DGUOK mutations (17%) in patients with hepatic involvement and combined respiratory chain deficiencies with hepatic involvement.
authors.affiliation: Laboratoire de Biochimie 1, APHP, hôpital de Bicêtre, Le Kremlin-Bicêtre, France. abdel.slama@bct.aphp.fr
authors.forename: A
authors.initials: A
authors.lastname: Slama
authors.forename: I
authors.initials: I
authors.lastname: Giurgea
authors.forename: D
authors.initials: D
authors.lastname: Debrey
authors.forename: D
authors.initials: D
authors.lastname: Bridoux
authors.forename: P
authors.initials: P
authors.lastname: de Lonlay
authors.forename: P
authors.initials: P
authors.lastname: Levy
authors.forename: D
authors.initials: D
authors.lastname: Chretien
authors.forename: M
authors.initials: M
authors.lastname: Brivet
authors.forename: A
authors.initials: A
authors.lastname: Legrand
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: A
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D008099:Liver / Q000503:physiopathology; D008297:Male; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D004272:DNA, Mitochondrial; D004247:DNA; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase