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L. Iommarini, A. Achilli, F. Pizza, C. La Morgia, M. L. Valentino, D. Bonneau, P. Amati-Bonneau, A. Torroni, V. Carelli; Validation of Rare Mitochondrial DNA Point Mutations Pathogenic for Leber’s Hereditary Optic Neuropathy (LHON). Invest. Ophthalmol. Vis. Sci. 2008;49(13):1308.
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© ARVO (1962-2015); The Authors (2016-present)
LHON is associated in 90% of patients with one of the three common mutations 11778/ND4, 3460/ND1 and 14484/ND6 (complex I subunit genes) in mitochondrial DNA (mtDNA). A small subset of LHON cases harbours different mtDNA mutations. We here describe and validate six rare LHON pathogenic mutations.
We sequenced the entire mtDNA in eight probands, who fulfilled the criteria for being considered LHON patients. In each case a candidate pathogenic mutation was found, based on its absence from the known datasets of population specific polymorphisms, and being previously reported in association with LHON at least once. Protein sequences were obtained by a BLAST search and aligned by ClustalX. We calculated the percentage of amino acid conservation and we set the value of 70% as conservation threshold. We used the PolyPhen tool to predict the possible impact of an amino acid change.
We found the 14568/ND6 mutation in three cases (haplogroups U6a1, K1a and J1c), and the 14459/ND6 (J1c), 14495/ND6 (H), 10663/ND4L (L2a), 3700/ND1 (H), and 4171/ND1 (J2b) in each remaining patient. One of the 14568/ND6 cases, as well as the 14495/ND6 and 4171/ND1 cases were heteroplasmic. Three out of the eight LHON cases were on haplogroup J (37.5%, versus 7.2% in control European population). Considering all eukaryotic sequences only 2 mutations (14495/ND6 and 3700/ND1) were above the conservation threshold. However, conservation of all mutations increased going to vertebrates, and then only mammals. In the latter case the conservation for all mutations ranged between 97.6% and 100% (invariant position). PolyPhen predicted as probably damaging the 14459/ND6 and 14495/ND6 mutations, similar to the 11778/ND4 and 14484/ND6 classic pathogenic mutations.
The 14568/ND6 mutation is the most frequent rare LHON pathogenic mutation. This study confirms that the ND6 gene is a mutational hot spot for LHON, and that the haplopgroup J is a modifying mtDNA background. All the other mutations were previously described at least once and this study validates their strict pathogenic association with LHON, suggesting their screening in LHON cases negative for the common mutations.
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