Functional characterization of three concomitant MtDNA LHON mutations shows no synergistic effect on mitochondrial activity

This is an open access article distributed under the terms of the Creative Commons Attribution License.-- et al.The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Leber's hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations.This work was supported by Instituto de Salud Carlos III, http://www.isciii.es/, PI 04/1001 to M.A.F.M.; Instituto de Salud Carlos III, http://www.isciii.es/, PI12/01683 to M.A.M.; Instituto de Salud Carlos III, http://www.isciii.es/, PI13/00556 to R.G.; Comunidad Autónoma de Madrid, http://www.madrid.org/cs/Satellite?pagename=ComunidadMadrid/Home, S2010/BMD-2402 to R.G.; Fundación Mutua Madrileña, http://www.fundacionmutua.es/, 10.04.02.0064 to M.A.F.M.; The Spanish Ministry of Economy and Competitiveness, http://www.mineco.gob.es/, BFU2011-25763 to J.A.; FEDER funds from the E.U. to R.G., http://ec.europa.eu/regional_policy/es/funding/erdf/.Peer Reviewe

Functional Characterization of Three Concomitant MtDNA LHON Mutations Shows No Synergistic Effect on Mitochondrial Activity.

The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Leber's hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations