Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder

Alexander J. Abrams, Robert B. Hufnagel, Adriana Rebelo, Claudia Zanna, Neville Patel, Michael A. Gonzalez, Ion J. Campeanu, Laurie B. Griffin, Saskia Groenewald, Alleene V. Strickland, Feifei Tao, Fiorella Speziani, Lisa Abreu, Rebecca Schüle, Leonardo Caporali, Chiara La Morgia, Alessandra Maresca, Rocco Liguori, Raffaele Lodi, Zubair M. AhmedKristen L. Sund, Xinjian Wang, Laura A. Krueger, Yanyan Peng, Carlos E. Prada, Cynthia A. Prows, Elizabeth K. Schorry, Anthony Antonellis, Holly H. Zimmerman, Omar A. Abdul-Rahman, Yaping Yang, Susan M. Downes, Jeffery Prince, Flavia Fontanesi, Antonio Barrientos, Andrea H. Németh, Valerio Carelli, Taosheng Huang, Stephan Zuchner, Julia E. Dallman

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

Original languageEnglish (US)
Pages (from-to)926-932
Number of pages7
JournalNature Genetics
Volume47
Issue number8
DOIs
StatePublished - Aug 30 2015

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Mitochondrial Dynamics
Optic Atrophy
Autosomal Dominant Optic Atrophy
Exome
Mutation
Mitochondrial Genes
Mitochondrial Membranes
Peripheral Nervous System Diseases
Zebrafish
Neurodegenerative Diseases
Cultured Cells
Tooth
Carrier Proteins
Membrane Proteins
Fishes
Proteins
Yeasts
Maintenance
Neurons

ASJC Scopus subject areas

  • Genetics

Cite this

Abrams, A. J., Hufnagel, R. B., Rebelo, A., Zanna, C., Patel, N., Gonzalez, M. A., ... Dallman, J. E. (2015). Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nature Genetics, 47(8), 926-932. https://doi.org/10.1038/ng.3354

Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. / Abrams, Alexander J.; Hufnagel, Robert B.; Rebelo, Adriana; Zanna, Claudia; Patel, Neville; Gonzalez, Michael A.; Campeanu, Ion J.; Griffin, Laurie B.; Groenewald, Saskia; Strickland, Alleene V.; Tao, Feifei; Speziani, Fiorella; Abreu, Lisa; Schüle, Rebecca; Caporali, Leonardo; La Morgia, Chiara; Maresca, Alessandra; Liguori, Rocco; Lodi, Raffaele; Ahmed, Zubair M.; Sund, Kristen L.; Wang, Xinjian; Krueger, Laura A.; Peng, Yanyan; Prada, Carlos E.; Prows, Cynthia A.; Schorry, Elizabeth K.; Antonellis, Anthony; Zimmerman, Holly H.; Abdul-Rahman, Omar A.; Yang, Yaping; Downes, Susan M.; Prince, Jeffery; Fontanesi, Flavia; Barrientos, Antonio; Németh, Andrea H.; Carelli, Valerio; Huang, Taosheng; Zuchner, Stephan; Dallman, Julia E.

In: Nature Genetics, Vol. 47, No. 8, 30.08.2015, p. 926-932.

Research output: Contribution to journalArticle

Abrams, AJ, Hufnagel, RB, Rebelo, A, Zanna, C, Patel, N, Gonzalez, MA, Campeanu, IJ, Griffin, LB, Groenewald, S, Strickland, AV, Tao, F, Speziani, F, Abreu, L, Schüle, R, Caporali, L, La Morgia, C, Maresca, A, Liguori, R, Lodi, R, Ahmed, ZM, Sund, KL, Wang, X, Krueger, LA, Peng, Y, Prada, CE, Prows, CA, Schorry, EK, Antonellis, A, Zimmerman, HH, Abdul-Rahman, OA, Yang, Y, Downes, SM, Prince, J, Fontanesi, F, Barrientos, A, Németh, AH, Carelli, V, Huang, T, Zuchner, S & Dallman, JE 2015, 'Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder', Nature Genetics, vol. 47, no. 8, pp. 926-932. https://doi.org/10.1038/ng.3354
Abrams AJ, Hufnagel RB, Rebelo A, Zanna C, Patel N, Gonzalez MA et al. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nature Genetics. 2015 Aug 30;47(8):926-932. https://doi.org/10.1038/ng.3354
Abrams, Alexander J. ; Hufnagel, Robert B. ; Rebelo, Adriana ; Zanna, Claudia ; Patel, Neville ; Gonzalez, Michael A. ; Campeanu, Ion J. ; Griffin, Laurie B. ; Groenewald, Saskia ; Strickland, Alleene V. ; Tao, Feifei ; Speziani, Fiorella ; Abreu, Lisa ; Schüle, Rebecca ; Caporali, Leonardo ; La Morgia, Chiara ; Maresca, Alessandra ; Liguori, Rocco ; Lodi, Raffaele ; Ahmed, Zubair M. ; Sund, Kristen L. ; Wang, Xinjian ; Krueger, Laura A. ; Peng, Yanyan ; Prada, Carlos E. ; Prows, Cynthia A. ; Schorry, Elizabeth K. ; Antonellis, Anthony ; Zimmerman, Holly H. ; Abdul-Rahman, Omar A. ; Yang, Yaping ; Downes, Susan M. ; Prince, Jeffery ; Fontanesi, Flavia ; Barrientos, Antonio ; Németh, Andrea H. ; Carelli, Valerio ; Huang, Taosheng ; Zuchner, Stephan ; Dallman, Julia E. / Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. In: Nature Genetics. 2015 ; Vol. 47, No. 8. pp. 926-932.
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abstract = "Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.",
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AU - Abrams, Alexander J.

AU - Hufnagel, Robert B.

AU - Rebelo, Adriana

AU - Zanna, Claudia

AU - Patel, Neville

AU - Gonzalez, Michael A.

AU - Campeanu, Ion J.

AU - Griffin, Laurie B.

AU - Groenewald, Saskia

AU - Strickland, Alleene V.

AU - Tao, Feifei

AU - Speziani, Fiorella

AU - Abreu, Lisa

AU - Schüle, Rebecca

AU - Caporali, Leonardo

AU - La Morgia, Chiara

AU - Maresca, Alessandra

AU - Liguori, Rocco

AU - Lodi, Raffaele

AU - Ahmed, Zubair M.

AU - Sund, Kristen L.

AU - Wang, Xinjian

AU - Krueger, Laura A.

AU - Peng, Yanyan

AU - Prada, Carlos E.

AU - Prows, Cynthia A.

AU - Schorry, Elizabeth K.

AU - Antonellis, Anthony

AU - Zimmerman, Holly H.

AU - Abdul-Rahman, Omar A.

AU - Yang, Yaping

AU - Downes, Susan M.

AU - Prince, Jeffery

AU - Fontanesi, Flavia

AU - Barrientos, Antonio

AU - Németh, Andrea H.

AU - Carelli, Valerio

AU - Huang, Taosheng

AU - Zuchner, Stephan

AU - Dallman, Julia E.

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N2 - Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

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