title: De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency.
abstract: Both nuclear and mitochondrial DNA mutations can cause energy generation disorders. Respiratory chain complex I deficiency is the most common energy generation disorder and a frequent cause of infantile mitochondrial encephalopathies such as Leigh's disease and lethal infantile mitochondrial disease. Most such cases have been assumed to be caused by nuclear gene defects, but recently an increasing number have been shown to be caused by mutations in the mitochondrially encoded complex I subunit genes ND4, ND5, and ND6. We report the first four cases of infantile mitochondrial encephalopathies caused by mutations in the ND3 subunit gene. Three unrelated children have the same novel heteroplasmic mutation (T10158C), only the second mutation reported in ND3, and one has the previously identified T10191C mutation. Both mutations cause disproportionately greater reductions in enzyme activity than in the amount of fully assembled complex I, suggesting the ND3 subunit plays an unknown but important role in electron transport, proton pumping, or ubiquinone binding. Three cases appear to have a de novo mutation, with no mutation detected in maternal relatives. Mitochondrial DNA disease may be considerably more prevalent in the pediatric population than currently predicted and should be considered in patients with infantile mitochondrial encephalopathies and complex I deficiency.
authors.affiliation: Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kirby
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Fowler
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.forename: Janice M
authors.initials: JM
authors.lastname: Fletcher
authors.forename: Joanne W
authors.initials: JW
authors.lastname: Dixon
authors.forename: Felicity A
authors.initials: FA
authors.lastname: Collins
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
mesh_terms: D015153:Blotting, Western; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000032:analysis; D042967:Electron Transport Complex I / Q000172:deficiency*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007888:Leigh Disease / Q000235:genetics; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011506:Proteins / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D011506:Proteins; D042967:Electron Transport Complex I; C114961:MT-ND3 protein, human