SSBP1 mutations in dominant optic atrophy with variable retinal degeneration

Jurkute, N., Leu, C., Pogoda, H.M., Arno, G., Robson, A.G., Nürnberg, G., Altmüller, J., Thiele, H., Motameny, S., Toliat, M.R., Powell, K., Höhne, W., Michaelides, M., Webster, A.R., Moore, A.T., Hammerschmidt, M., Nürnberg, P., Yu-Wai-Man, P., Votruba, M.
Annals of neurology   86(3): 368-383 (Journal)
Registered Authors
Hammerschmidt, Matthias, Pogoda, Hans-Martin
MeSH Terms
  • Animals
  • Cell Differentiation/genetics
  • Cells, Cultured
  • DNA-Binding Proteins/genetics*
  • Female
  • Gene Knockdown Techniques
  • Genetic Linkage/genetics
  • Genetic Predisposition to Disease/genetics*
  • Humans
  • Male
  • Mice
  • Mitochondrial Proteins/genetics*
  • Mutation, Missense
  • Optic Atrophy, Autosomal Dominant/genetics*
  • Optic Atrophy, Autosomal Dominant/pathology
  • Pedigree
  • RNA, Messenger/genetics
  • Retinal Degeneration/genetics
  • Retinal Degeneration/pathology
  • Zebrafish/genetics
31298765 Full text @ Ann. Neurol.
Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a proportion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality.
Linkage analysis and sequencing were performed in multi-generation families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.
We defined a new ADOA locus on 7q33-q35 and identified three different missense variants in SSBP1 (NM_001256510.1; c.113G>A (p.(Arg38Gln)), c.320G>A (p.(Arg107Gln)) and c.422G>A (p.(Ser141Asn))) in affected individuals from two families and two singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 to ssDNA. Antisense-mediated knockdown of endogenous ssbp1 mRNA in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point to an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in two multi-generation families studied.
SSBP1 is an essential protein for mtDNA replication and maintenance. Our data established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. This article is protected by copyright. All rights reserved.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes