Jurkute, Neringa ORCID: 0000-0002-3092-7451, Leu, Costin, Pogoda, Hans-Martin, Arno, Gavin, Robson, Anthony G., Nuernberg, Gudrun, Altmueller, Janine, Thiele, Holger, Motameny, Susanne, Toliat, Mohammad Reza, Powell, Kate, Hoehne, Wolfgang, Michaelides, Michel, Webster, Andrew R., Moore, Anthony T., Hammerschmidt, Matthias, Nuernberg, Peter, Yu-Wai-Man, Patrick and Votruba, Marcela ORCID: 0000-0002-7680-9135 (2019). SSBP1 mutations in dominant optic atrophy with variable retinal degeneration. Ann. Neurol., 86 (3). S. 368 - 384. HOBOKEN: WILEY. ISSN 1531-8249

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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 portion 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 multigeneration 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 3 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 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-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 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 ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied. Interpretation SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Jurkute, NeringaUNSPECIFIEDorcid.org/0000-0002-3092-7451UNSPECIFIED
Leu, CostinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pogoda, Hans-MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arno, GavinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robson, Anthony G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Powell, KateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michaelides, MichelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Webster, Andrew R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moore, Anthony T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu-Wai-Man, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Votruba, MarcelaUNSPECIFIEDorcid.org/0000-0002-7680-9135UNSPECIFIED
URN: urn:nbn:de:hbz:38-134428
DOI: 10.1002/ana.25550
Journal or Publication Title: Ann. Neurol.
Volume: 86
Number: 3
Page Range: S. 368 - 384
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1531-8249
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-BINDING-PROTEIN; ISCEV STANDARD; MITOCHONDRIAL; DATABASE; TRANSCRIPTION; LOCALIZATION; REPLICATION; DISORDERMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13442

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