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Title: Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy
Authors: Giordano, Carla
Iommarini, Luisa
Giordano, Luca
Maresca, Alessandra
Pisano, Annalinda
Valentino, Maria Lucia
Caporali, Leonardo
Liguori, Rocco
Deceglie, Stefania
Roberti, Marina
Fanelli, Francesca
Fracasso, Flavio
Ross-Cisneros, Fred N.
D'Adamo, Pio
Hudson, Gavin
Pyle, Angela
Yu-Wai-Man, Patrick
Chinnery, Patrick F.
Zeviani, Massimo
Salomão, Solange Rios [UNIFESP]
Berezovsky, Adriana [UNIFESP]
Belfort, Rubens Junior [UNIFESP]
Ventura, Dora Fix
Moraes, Milton Nunes de[UNIFESP]
Moraes-Filho, Milton Nunes de[UNIFESP]
Barboni, Piero
Sadun, Federico
De Negri, Annamaria
Sadun, Alfredo A.
Tancredi, Andrea
Mancini, Massimiliano
d'Amati, Giulia
Polosa, Paola Loguercio
Cantatore, Palmiro
Carelli, Valerio
Univ Rome
Univ Bologna
Univ Bari
Bellaria Hosp
Univ Trieste
Newcastle Univ
Fdn Ist Neurol Carlo Besta IRCCS
MRC Mitochondrial Biol Unit
Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Studio Oculist dAzeglio
Osped San Giovanni Evangelista
Azienda Osped San Camillo Forlanini
Keywords: LHON penetrance
mitochondrial biogenesis
mtDNA copy number
Issue Date: 1-Feb-2014
Publisher: Oxford Univ Press
Citation: Brain. Oxford: Oxford Univ Press, v. 137, p. 335-353, 2014.
Abstract: Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.
ISSN: 0006-8950
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Appears in Collections:Artigo

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