Jurkute, N;
Leu, C;
Pogoda, H-M;
Arno, G;
Robson, AG;
Nürnberg, G;
Altmüller, J;
... Votruba, M; + view all
(2019)
SSBP1 mutations in dominant optic atrophy with variable retinal degeneration.
Annals of Neurology
, 86
(3)
pp. 368-383.
10.1002/ana.25550.
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Abstract
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.
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