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Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.


ABSTRACT: 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.

SUBMITTER: Peng Y 

PROVIDER: S-EPMC5886230 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.

Peng Yanyan Y   Shinde Deepali N DN   Valencia C Alexander CA   Mo Jun-Song JS   Rosenfeld Jill J   Truitt Cho Megan M   Chamberlin Adam A   Li Zhuo Z   Liu Jie J   Gui Baoheng B   Brockhage Rachel R   Basinger Alice A   Alvarez-Leon Brenda B   Heydemann Peter P   Magoulas Pilar L PL   Lewis Andrea M AM   Scaglia Fernando F   Gril Solange S   Chong Shuk Ching SC   Bower Matthew M   Monaghan Kristin G KG   Willaert Rebecca R   Plona Maria-Renee MR   Dineen Rich R   Milan Francisca F   Hoganson George G   Powis Zoe Z   Helbig Katherine L KL   Keller-Ramey Jennifer J   Harris Belinda B   Anderson Laura C LC   Green Torrian T   Sukoff Rizzo Stacey J SJ   Kaylor Julie J   Chen Jiani J   Guan Min-Xin MX   Sellars Elizabeth E   Sparagana Steven P SP   Gibson James B JB   Reinholdt Laura G LG   Tang Sha S   Huang Taosheng T  

Human molecular genetics 20171201 24


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 m  ...[more]

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