title: A novel c.592-4_c.592-3delTT mutation in DGUOK gene causes exon skipping.
abstract: Deoxyguanosine kinase (DGUOK) catalyzes the first step of the mitochondrial deoxypurine salvage pathway, the phosphorylation of purine deoxyribonucleosides. Mutations in the DGUOK gene have been linked to inherited mtDNA depletion syndromes, neonatal liver failure, nystagmus, and hypotonia. Previously, we reported the first case of a heterozygous unclassified c.592-4_c.592-3delTT alteration in a patient with DGUOK deficiency without the demonstration of its pathogenicity (Dimmock et al., 2008). This alteration was predicted to cause aberrant splicing based upon two computer algorithms. We now report a homozygous c.592-4_c.592-3delTT mutation found in two affected siblings of asymptomatic consanguineous parents. The proband presented with symptoms of idiopathic hepatitis, liver dysfunction, nystagmus, and retinal blindness. This individual died at 6months of age due to liver failure. This individual's affected sibling presented similarly and has remarkable elevations of tyrosine, methionine, and alanine. Many organic acids were elevated in urine, including lactic acid, Krebs cycle intermediates, and para-hydroxy compounds; ketone bodies were also present. RNA studies support aberrant splicing. Sequencing of cDNA detected exon 5 skipping in the two affected siblings, but not in the normal control. These results indicate that the homozygous c.592-4_c.592-3delTT is deleterious and responsible for the DGUOK deficiency. The parents were subsequently confirmed to be carriers of this mutation. In summary, we have demonstrated that c.592-4_c.592-3delTT is a pathogenic splice acceptor site mutation leading to DGUOK deficiency.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jack Q
authors.initials: JQ
authors.lastname: Ji
authors.forename: David
authors.initials: D
authors.lastname: Dimmock
authors.forename: Lin-Ya
authors.initials: LY
authors.lastname: Tang
authors.forename: Maria
authors.initials: M
authors.lastname: Descartes
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomez
authors.forename: S Lane
authors.initials: SL
authors.lastname: Rutledge
authors.forename: Eric S
authors.initials: ES
authors.lastname: Schmitt
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D001483:Base Sequence; D001766:Blindness / Q000473:pathology; D018076:DNA, Complementary / Q000302:isolation & purification; D006505:Hepatitis / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007223:Infant; D028361:Mitochondrial Diseases / Q000473:pathology*; D008969:Molecular Sequence Data; D009759:Nystagmus, Pathologic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency*; D012326:RNA Splicing; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D035781:Siblings
chemical_list: D018076:DNA, Complementary; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase