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This study aimed to identify novel ADOA\u2010associated genes and explore their causality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease\u2010causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We defined a new ADOA locus on 7q33\u2010q35 and identified 3 different missense variants in <jats:italic>SSBP1<\/jats:italic> (NM_001256510.1; c.113G&gt;A [p.(Arg38Gln)], c.320G&gt;A [p.(Arg107Gln)] and c.422G&gt;A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single\u2010strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single\u2010strand DNA. Antisense\u2010mediated knockdown of endogenous <jats:italic>ssbp1<\/jats:italic> messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of <jats:italic>ssbp1<\/jats:italic> in retinal development and the dominant\u2010negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in <jats:italic>SSBP1<\/jats:italic> as a cause of ADOA and variable retinal degeneration. 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