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author Peng, Yanyan
Shinde, Deepali N
Valencia, C Alexander
Mo, Jun-Song
Rosenfeld, Jill
Truitt Cho, Megan
Chamberlin, Adam
Li, Zhuo
Liu, Jie
Gui, Baoheng
Brockhage, Rachel
Basinger, Alice
Alvarez-Leon, Brenda
Heydemann, Peter
Magoulas, Pilar L
Lewis, Andrea M
Scaglia, Fernando
Gril, Solange
Chong, Shuk Ching
Bower, Matthew
Monaghan, Kristin G
Willaert, Rebecca
Plona, Maria-Renee
Dineen, Rich
Milan, Francisca
Hoganson, George
Powis, Zoe
Helbig, Katherine L
Keller-Ramey, Jennifer
Harris, Belinda
Anderson, Laura C
Green, Torrian
Sukoff Rizzo, Stacey J
Kaylor, Julie
Chen, Jiani
Guan, Min-Xin
Sellars, Elizabeth
Sparagana, Steven P
Gibson, James B
Reinholdt, Laura G
Tang, Sha
Huang, Taosheng
author_facet Peng, Yanyan
Shinde, Deepali N
Valencia, C Alexander
Mo, Jun-Song
Rosenfeld, Jill
Truitt Cho, Megan
Chamberlin, Adam
Li, Zhuo
Liu, Jie
Gui, Baoheng
Brockhage, Rachel
Basinger, Alice
Alvarez-Leon, Brenda
Heydemann, Peter
Magoulas, Pilar L
Lewis, Andrea M
Scaglia, Fernando
Gril, Solange
Chong, Shuk Ching
Bower, Matthew
Monaghan, Kristin G
Willaert, Rebecca
Plona, Maria-Renee
Dineen, Rich
Milan, Francisca
Hoganson, George
Powis, Zoe
Helbig, Katherine L
Keller-Ramey, Jennifer
Harris, Belinda
Anderson, Laura C
Green, Torrian
Sukoff Rizzo, Stacey J
Kaylor, Julie
Chen, Jiani
Guan, Min-Xin
Sellars, Elizabeth
Sparagana, Steven P
Gibson, James B
Reinholdt, Laura G
Tang, Sha
Huang, Taosheng
author_sort Peng, Yanyan
collection PubMed
description Iron–sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe–S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.
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spelling pubmed-58862302018-04-09 Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy Peng, Yanyan Shinde, Deepali N Valencia, C Alexander Mo, Jun-Song Rosenfeld, Jill Truitt Cho, Megan Chamberlin, Adam Li, Zhuo Liu, Jie Gui, Baoheng Brockhage, Rachel Basinger, Alice Alvarez-Leon, Brenda Heydemann, Peter Magoulas, Pilar L Lewis, Andrea M Scaglia, Fernando Gril, Solange Chong, Shuk Ching Bower, Matthew Monaghan, Kristin G Willaert, Rebecca Plona, Maria-Renee Dineen, Rich Milan, Francisca Hoganson, George Powis, Zoe Helbig, Katherine L Keller-Ramey, Jennifer Harris, Belinda Anderson, Laura C Green, Torrian Sukoff Rizzo, Stacey J Kaylor, Julie Chen, Jiani Guan, Min-Xin Sellars, Elizabeth Sparagana, Steven P Gibson, James B Reinholdt, Laura G Tang, Sha Huang, Taosheng Hum Mol Genet Articles Iron–sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe–S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans. Oxford University Press 2017-12-15 2017-10-05 /pmc/articles/PMC5886230/ /pubmed/29040572 http://dx.doi.org/10.1093/hmg/ddx377 Text en © The Author 2017. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Articles
Peng, Yanyan
Shinde, Deepali N
Valencia, C Alexander
Mo, Jun-Song
Rosenfeld, Jill
Truitt Cho, Megan
Chamberlin, Adam
Li, Zhuo
Liu, Jie
Gui, Baoheng
Brockhage, Rachel
Basinger, Alice
Alvarez-Leon, Brenda
Heydemann, Peter
Magoulas, Pilar L
Lewis, Andrea M
Scaglia, Fernando
Gril, Solange
Chong, Shuk Ching
Bower, Matthew
Monaghan, Kristin G
Willaert, Rebecca
Plona, Maria-Renee
Dineen, Rich
Milan, Francisca
Hoganson, George
Powis, Zoe
Helbig, Katherine L
Keller-Ramey, Jennifer
Harris, Belinda
Anderson, Laura C
Green, Torrian
Sukoff Rizzo, Stacey J
Kaylor, Julie
Chen, Jiani
Guan, Min-Xin
Sellars, Elizabeth
Sparagana, Steven P
Gibson, James B
Reinholdt, Laura G
Tang, Sha
Huang, Taosheng
Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy
title Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy
title_full Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy
title_fullStr Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy
title_full_unstemmed Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy
title_short Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy
title_sort biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886230/
https://www.ncbi.nlm.nih.gov/pubmed/29040572
http://dx.doi.org/10.1093/hmg/ddx377
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