SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder: Journal of Clinical Investigation

V. Del Dotto, F. Ullah, I. Di Meo, P. Magini, M. Gusic, A. Maresca, L. Caporali, F. Palombo, F. Tagliavini, E.H. Baugh, B. MacAo, Z. Szilagyi, C. Peron, M.A. Gustafson, K. Khan, C. La Morgia, P. Barboni, M. Carbonelli, M.L. Valentino, R. LiguoriV. Shashi, J. Sullivan, S. Nagaraj, M. El-Dairi, A. Iannaccone, I. Cutcutache, E. Bertini, R. Carrozzo, F. Emma, F. Diomedi-Camassei, C. Zanna, M. Armstrong, M. Page, N. Stong, S. Boesch, R. Kopajtich, S. Wortmann, W. Sperl, E.E. Davis, W.C. Copeland, M. Seri, M. Falkenberg, H. Prokisch, N. Katsanis, V. Tiranti, T. Pippucci, V. Carelli

Research output: Contribution to journalArticlepeer-review


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 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as 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 WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology. © 2020 American Society for Clinical Investigation.
Original languageEnglish
Pages (from-to)108-125
Number of pages18
JournalJ. Clin. Invest.
Issue number1
Publication statusPublished - 2020


  • cytochrome c oxidase
  • messenger RNA
  • mitochondrial DNA
  • protein
  • single strand binding protein 1
  • single stranded DNA
  • unclassified drug
  • voltage dependent anion channel 1
  • DNA binding protein
  • DNA directed DNA polymerase gamma
  • mitochondrial protein
  • SSBP1 protein, human
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • bioenergy
  • clinical article
  • clinical feature
  • comparative study
  • controlled study
  • DNA content
  • dominant inheritance
  • droplet digital polymerase chain reaction
  • embryo
  • ex vivo study
  • female
  • gene expression
  • gene segregation
  • genetic transcription
  • histopathology
  • homozygosity
  • human
  • human cell
  • human tissue
  • immunofluorescence
  • in vivo study
  • kidney biopsy
  • kidney failure
  • limit of quantitation
  • macular degeneration
  • male
  • missense mutation
  • mitochondrial DNA depletion
  • mitochondrial DNA replication
  • mitochondrial myopathy
  • muscle biopsy
  • mutation
  • nonhuman
  • optic nerve atrophy
  • perception deafness
  • phenotype
  • photoreceptor
  • phylogeny
  • priority journal
  • protein conformation
  • protein cross linking
  • protein stability
  • recessive inheritance
  • replisome
  • retinal pigment epithelium
  • skeletal muscle
  • skin fibroblast
  • whole exome sequencing
  • zebra fish
  • animal
  • chemistry
  • DNA replication
  • exome
  • genetics
  • hereditary optic atrophy
  • metabolism
  • mitochondrion
  • physiology
  • Animals
  • DNA Polymerase gamma
  • DNA Replication
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Exome
  • Female
  • Humans
  • Male
  • Mitochondria
  • Mitochondrial Proteins
  • Mutation
  • Optic Atrophies, Hereditary
  • Zebrafish


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