Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia

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...

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Bibliographic Details
Published in:American journal of human genetics 1996-04, Vol.58 (4), p.703-711
Main Authors: De Vries, D D, Went, L N, Bruyn, G W, Scholte, H R, Hofstra, R M, Bolhuis, P A, van Oost, B A
Format: Article
Language:English
Subjects:
Adult
Amino Acid Sequence
Citrate (si)-Synthase - metabolism
DNA Mutational Analysis
DNA, Mitochondrial - genetics
Dystonia - complications
Dystonia - enzymology
Dystonia - genetics
Electron Transport
Female
Gene Frequency
Humans
Male
Middle Aged
Molecular Sequence Data
Muscle, Skeletal - enzymology
NAD(P)H Dehydrogenase (Quinone) - deficiency
NAD(P)H Dehydrogenase (Quinone) - genetics
NADH Dehydrogenase - genetics
Optic Atrophies, Hereditary - complications
Optic Atrophies, Hereditary - enzymology
Optic Atrophies, Hereditary - genetics
Oxidoreductases - metabolism
Pedigree
Phenotype
Point Mutation - genetics
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Summary: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.
ISSN:0002-9297
1537-6605