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Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914475/ https://www.ncbi.nlm.nih.gov/pubmed/24369379 http://dx.doi.org/10.1093/brain/awt343 |
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author | 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 Salomao, Solange R. Berezovsky, Adriana Belfort, Rubens Ventura, Dora Fix Moraes, Milton Moraes Filho, Milton Barboni, Piero Sadun, Federico De Negri, Annamaria Sadun, Alfredo A. Tancredi, Andrea Mancini, Massimiliano d’Amati, Giulia Loguercio Polosa, Paola Cantatore, Palmiro Carelli, Valerio |
author_facet | 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 Salomao, Solange R. Berezovsky, Adriana Belfort, Rubens Ventura, Dora Fix Moraes, Milton Moraes Filho, Milton Barboni, Piero Sadun, Federico De Negri, Annamaria Sadun, Alfredo A. Tancredi, Andrea Mancini, Massimiliano d’Amati, Giulia Loguercio Polosa, Paola Cantatore, Palmiro Carelli, Valerio |
author_sort | Giordano, Carla |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3914475 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-39144752014-02-05 Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy 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 Salomao, Solange R. Berezovsky, Adriana Belfort, Rubens Ventura, Dora Fix Moraes, Milton Moraes Filho, Milton Barboni, Piero Sadun, Federico De Negri, Annamaria Sadun, Alfredo A. Tancredi, Andrea Mancini, Massimiliano d’Amati, Giulia Loguercio Polosa, Paola Cantatore, Palmiro Carelli, Valerio Brain Original Articles 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. Oxford University Press 2014-02 2013-12-24 /pmc/articles/PMC3914475/ /pubmed/24369379 http://dx.doi.org/10.1093/brain/awt343 Text en © The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles 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 Salomao, Solange R. Berezovsky, Adriana Belfort, Rubens Ventura, Dora Fix Moraes, Milton Moraes Filho, Milton Barboni, Piero Sadun, Federico De Negri, Annamaria Sadun, Alfredo A. Tancredi, Andrea Mancini, Massimiliano d’Amati, Giulia Loguercio Polosa, Paola Cantatore, Palmiro Carelli, Valerio Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy |
title | Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy |
title_full | Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy |
title_fullStr | Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy |
title_full_unstemmed | Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy |
title_short | Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy |
title_sort | efficient mitochondrial biogenesis drives incomplete penetrance in leber’s hereditary optic neuropathy |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914475/ https://www.ncbi.nlm.nih.gov/pubmed/24369379 http://dx.doi.org/10.1093/brain/awt343 |
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