SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder

Del Dotto, V., Ullah, F., Di Meo, I., Magini, P., Gusic, M., Maresca, A., Caporali, L., Palombo, F., Tagliavini, F., Baugh, E.H., Macao, B., Szilagyi, Z., Péron, C., Gustafson, M.A., Khan, K., La Morgia, C., Barboni, P., Carbonelli, M., Valentino, M.L., Liguori, R., Shashi, V., Sullivan, J.A., Nagaraj, S., El-Dairi, M., Iannaccone, A., Cutcutache, I., Bertini, E., Carrozzo, R., Emma, F., Diomedi-Camassei, F., Zanna, C., Armstrong, M., Page, M.J., Boesch, S., Wortmann, S.B., Kopajtich, R., Stong, N., Sperl, W., Davis, E., Copeland, W.C., Seri, M., Falkenberg, M., Prokisch, H., Katsanis, N., Tiranti, V., Pippucci, T., Carelli, V.
The Journal of Clinical Investigation   130(1): 108-125 (Journal)
Registered Authors
Bioenergetics, Genetic diseases, Genetics, Mitochondria, Ophthalmology
MeSH Terms
  • Animals
  • DNA Polymerase gamma/physiology
  • DNA Replication
  • DNA, Mitochondrial/genetics*
  • DNA-Binding Proteins/chemistry
  • DNA-Binding Proteins/genetics*
  • Exome
  • Female
  • Humans
  • Male
  • Mitochondria/metabolism
  • Mitochondrial Proteins/chemistry
  • Mitochondrial Proteins/genetics*
  • Mutation*
  • Optic Atrophies, Hereditary/etiology
  • Optic Atrophies, Hereditary/genetics*
  • Zebrafish
31550240 Full text @ Journal of Clin. Invest.
Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single strand binding protein (SSBP1) in four families with dominant and one with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect its amount and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids and 7S-DNA amounts as well as mtDNA replication, impacting replisome machinery. The variable mtDNA depletion in cells reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits and complexes amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex-vivo in biopsies of affected tissues, like kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by wild-type mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as cause of human pathology.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes