Ophthalmologic Findings in Leber Hereditary Optic Neuropathy, With Special Reference to mtDNA Mutations

Ek, Nikoskelainen; Huoponen, Kirsi; Juvonen,; Lamminen, Tarja; Nummelin, Kari; Savontaus, Marja Liisa

doi:10.1097/00041327-199703000-00027

Cited by 120 publications

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Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

et al. 2001

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Leber hereditary optic neuropathy (LHON) is a major cause of inherited blindness in young males. Approximately 1 in 7 individuals with LHON harbor a mixture of mutated and wild-type (normal) mtDNA (heteroplasmy), and the risks of developing blindness in heteroplasmic LHON individuals are not well characterized. MtDNA is inherited exclusively down the maternal line, and although the risks of a relative within a homoplasmic LHON pedigree are relatively well established, the risks of transmission in heteroplasmic LHON pedigrees have not been studied in detail. We analyzed 17 independent pedigrees that harbor the most prevalent LHON mutation: G11778A. The pedigrees were influenced by incomplete ascertainment bias, which was reduced by omitting the affected probands from the analysis. We made the following observations: (1) The frequency of blindness in males was related to the mutation load in that individual's blood. (2) Mothers with < or = 80% mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift in these pedigrees. This study provides insights into the mutation load, or threshold, necessary for expression of the optic neuropathy, the relationship between mutation load in the mother and the risk of blindness in her children, and the complex inheritance of heteroplasmic mtDNA defects.

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Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

et al. 2001

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Biochemical features of mtDNA 14484 (ND6/m64V) point mutation associated with Leber's hereditary optic neuropathy

et al. 1999

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We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene. The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I–specific activity and increases the sensitivity to the product decylubiquinol. Given the proximity of both mutations in the ND6 gene, we tested the specific activity of complex I and its sensitivity to myxothiazol and nonylbenzoquinol, both inhibitors at the ubiquinol product site, in platelet submitochondrial particles from nine 14484 homoplasmic individuals, 8 Italians with Caucasian mtDNA haplogroup J (adjunctive 4216 and 13708 mutations), and 1 Tunisian with an African mtDNA haplogroup. The specific activity of complex I was not affected by the 14484 mutation, but the sensitivity to both inhibitors was significantly increased compared with control subjects regardless of the presence of haplogroup J polymorphisms. Analysis of 70 different amino acid sequences of the ND6 subunit indicated that the 14484 mutation affects an amino acid belonging to its most conserved region, which shows local similarities with cytochrome b regions interacting with ubiquinone or ubiquinol in complex III. Our results suggest that both 14484 and 14459 mutations may affect amino acids forming the interaction site of ubiquinol product, and the 14484 mutation produces a biochemical defect resembling in part that already reported for the common 11778/ND4 LHON mutation. Ann Neurol 1999;45:320–328

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Optic Neuropathies

Kidd

2017

Neurodegeneration

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Ophthalmologic Findings in Leber Hereditary Optic Neuropathy, With Special Reference to mtDNA Mutations

Cited by 120 publications

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Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

Biochemical features of mtDNA 14484 (ND6/m64V) point mutation associated with Leber's hereditary optic neuropathy

Optic Neuropathies

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