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

Abrams, A.J., Hufnagel, R.B., Rebelo, A., Zanna, C., Patel, N., Gonzalez, M.A., Campeanu, I.J., Griffin, L.B., Groenewald, S., Strickland, A.V., Tao, F., Speziani, F., Abreu, L., Schüle, R., Caporali, L., La Morgia, C., Maresca, A., Liguori, R., Lodi, R., Ahmed, Z.M., Sund, K.L., Wang, X., Krueger, L.A., Peng, Y., Prada, C.E., Prows, C.A., Schorry, E.K., Antonellis, A., Zimmerman, H.H., Abdul-Rahman, O.A., Yang, Y., Downes, S.M., Prince, J., Fontanesi, F., Barrientos, A., Németh, A.H., Carelli, V., Huang, T., Zuchner, S., Dallman, J.E.
Nature Genetics   47(8): 926-32 (Journal)
Registered Authors
Dallman, Julia
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • COS Cells
  • Charcot-Marie-Tooth Disease/genetics
  • Charcot-Marie-Tooth Disease/metabolism
  • Chlorocebus aethiops
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/ultrastructure
  • Exome/genetics
  • Female
  • Genetic Predisposition to Disease/genetics*
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Mitochondrial Membranes/metabolism
  • Mitochondrial Proteins/genetics*
  • Mitochondrial Proteins/metabolism
  • Muscle Proteins/genetics
  • Muscle Proteins/metabolism
  • Mutation*
  • Optic Atrophy, Autosomal Dominant/genetics*
  • Optic Atrophy, Autosomal Dominant/metabolism
  • Optic Atrophy, Autosomal Dominant/pathology
  • Pedigree
  • Phosphate Transport Proteins/genetics*
  • Phosphate Transport Proteins/metabolism
  • Protein Binding
  • RNA Interference
  • Saccharomyces cerevisiae Proteins/genetics
  • Saccharomyces cerevisiae Proteins/metabolism
  • Sequence Analysis, DNA
  • Zebrafish/embryology
  • Zebrafish/metabolism
26168012 Full text @ Nat. Genet.
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.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes