title: Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia.
abstract: A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-->A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy.
authors.affiliation: Department of Pediatrics and Human Genetics, University Hospital Nijmegen, The Netherlands.
authors.forename: D D
authors.initials: DD
authors.lastname: De Vries
authors.forename: L N
authors.initials: LN
authors.lastname: Went
authors.forename: G W
authors.initials: GW
authors.lastname: Bruyn
authors.forename: H R
authors.initials: HR
authors.lastname: Scholte
authors.forename: R M
authors.initials: RM
authors.lastname: Hofstra
authors.forename: P A
authors.initials: PA
authors.lastname: Bolhuis
authors.forename: B A
authors.initials: BA
authors.lastname: van Oost
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004421:Dystonia / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D004579:Electron Transport; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency* / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D010088:Oxidoreductases / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D010088:Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); D009245:NADH Dehydrogenase; D002950:Citrate (si)-Synthase