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
- Cell Differentiation/genetics
- Cells, Cultured
- DNA-Binding Proteins/genetics*
- Gene Knockdown Techniques
- Genetic Linkage/genetics
- Genetic Predisposition to Disease/genetics*
- Mitochondrial Proteins/genetics*
- Mutation, Missense
- Optic Atrophy, Autosomal Dominant/genetics*
- Optic Atrophy, Autosomal Dominant/pathology
- RNA, Messenger/genetics
- Retinal Degeneration/genetics
- Retinal Degeneration/pathology
- 31298765 Full text @ Ann. Neurol.
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. (2019) SSBP1 mutations in dominant optic atrophy with variable retinal degeneration. Annals of neurology. 86(3):368-383.
Objective 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.
Methods 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.
Results 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.
Interpretation 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
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes