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

Yanyan Peng, Deepali N. Shinde, C. Alexander Valencia, Jun Song Mo, Jill Rosenfeld, Megan Truitt Cho, Adam Chamberlin, Zhuo Li, Jie Liu, Baoheng Gui, Rachel Brockhage, Alice Basinger, Brenda Alvarez-Leon, Peter Heydemann, Pilar L. Magoulas, Andrea M. Lewis, Fernando Scaglia, Solange Gril, Shuk Ching Chong, Matthew BowerKristin G. Monaghan, Rebecca Willaert, Maria Renee Plona, Rich Dineen, Francisca Milan, George Hoganson, Zoe Powis, Katherine L. Helbig, Jennifer Keller-Ramey, Belinda Harris, Laura C. Anderson, Torrian Green, Stacey J. Sukoff Rizzo, Julie Kaylor, Jiani Chen, Min Xin Guan, Elizabeth Sellars, Steven P. Sparagana, James B. Gibson, Laura G. Reinholdt, Sha Tang, Taosheng Huang

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4937-4950
Number of pages14
JournalHuman Molecular Genetics
Volume26
Issue number24
DOIs
StatePublished - Dec 1 2017

Fingerprint

Optic Atrophy
Ferredoxins
Oxidoreductases
Mutation
Iron
Ferredoxin-NADP Reductase
Genes
Exome
Flavoproteins
Germ-Line Mutation
Enzyme Assays
Mitochondrial Membranes
Electron Transport
Mitochondrial DNA
NADP
Gait
Sulfur
Oxygen Consumption
DNA Repair
Cytochrome P-450 Enzyme System

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Peng, Y., Shinde, D. N., Valencia, C. A., Mo, J. S., Rosenfeld, J., Cho, M. T., ... Huang, T. (2017). Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy. Human Molecular Genetics, 26(24), 4937-4950. https://doi.org/10.1093/hmg/ddx377

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; Cho, Megan Truitt; 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.

In: Human Molecular Genetics, Vol. 26, No. 24, 01.12.2017, p. 4937-4950.

Research output: Contribution to journalArticle

Peng, Y, Shinde, DN, Valencia, CA, Mo, JS, Rosenfeld, J, Cho, MT, Chamberlin, A, Li, Z, Liu, J, Gui, B, Brockhage, R, Basinger, A, Alvarez-Leon, B, Heydemann, P, Magoulas, PL, Lewis, AM, Scaglia, F, Gril, S, Chong, SC, Bower, M, Monaghan, KG, Willaert, R, Plona, MR, Dineen, R, Milan, F, Hoganson, G, Powis, Z, Helbig, KL, Keller-Ramey, J, Harris, B, Anderson, LC, Green, T, Sukoff Rizzo, SJ, Kaylor, J, Chen, J, Guan, MX, Sellars, E, Sparagana, SP, Gibson, JB, Reinholdt, LG, Tang, S & Huang, T 2017, 'Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy', Human Molecular Genetics, vol. 26, no. 24, pp. 4937-4950. https://doi.org/10.1093/hmg/ddx377
Peng, Yanyan ; Shinde, Deepali N. ; Valencia, C. Alexander ; Mo, Jun Song ; Rosenfeld, Jill ; Cho, Megan Truitt ; 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. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 24. pp. 4937-4950.
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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.",
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T1 - Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy

AU - Peng, Yanyan

AU - Shinde, Deepali N.

AU - Valencia, C. Alexander

AU - Mo, Jun Song

AU - Rosenfeld, Jill

AU - Cho, Megan Truitt

AU - Chamberlin, Adam

AU - Li, Zhuo

AU - Liu, Jie

AU - Gui, Baoheng

AU - Brockhage, Rachel

AU - Basinger, Alice

AU - Alvarez-Leon, Brenda

AU - Heydemann, Peter

AU - Magoulas, Pilar L.

AU - Lewis, Andrea M.

AU - Scaglia, Fernando

AU - Gril, Solange

AU - Chong, Shuk Ching

AU - Bower, Matthew

AU - Monaghan, Kristin G.

AU - Willaert, Rebecca

AU - Plona, Maria Renee

AU - Dineen, Rich

AU - Milan, Francisca

AU - Hoganson, George

AU - Powis, Zoe

AU - Helbig, Katherine L.

AU - Keller-Ramey, Jennifer

AU - Harris, Belinda

AU - Anderson, Laura C.

AU - Green, Torrian

AU - Sukoff Rizzo, Stacey J.

AU - Kaylor, Julie

AU - Chen, Jiani

AU - Guan, Min Xin

AU - Sellars, Elizabeth

AU - Sparagana, Steven P.

AU - Gibson, James B.

AU - Reinholdt, Laura G.

AU - Tang, Sha

AU - Huang, Taosheng

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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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