Scrutinizing pathogenicity of the USH2A c.2276 G > T; p.(Cys759Phe) variant.

Autor: Reurink J; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., de Vrieze E; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., Li CHZ; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands., van Berkel E; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Broekman S; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., Aben M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Peters T; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., Oostrik J; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., Neveling K; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Venselaar H; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Ramos MG; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Gilissen C; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Astuti GDN; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University, Semarang, Indonesia., Galbany JC; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., van Lith-Verhoeven JJC; Department of Ophthalmology, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands., Ockeloen CW; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Haer-Wigman L; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Hoyng CB; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands., Cremers FPM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Kremer H; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., Roosing S; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. Susanne.Roosing@radboudumc.nl.; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Susanne.Roosing@radboudumc.nl., van Wijk E; Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Erwin.vanWyk@radboudumc.nl.; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands. Erwin.vanWyk@radboudumc.nl.
Jazyk: angličtina
Zdroj: NPJ genomic medicine [NPJ Genom Med] 2022 Jun 07; Vol. 7 (1), pp. 37. Date of Electronic Publication: 2022 Jun 07.
DOI: 10.1038/s41525-022-00306-z
Abstrakt: The USH2A variant c.2276 G > T (p.(Cys759Phe)) has been described by many authors as a frequent cause of autosomal recessive retinitis pigmentosa (arRP). However, this is in contrast with the description of two asymptomatic individuals homozygous for this variant. We therefore assessed pathogenicity of the USH2A c.2276 G > T variant using extensive genetic and functional analyses. Whole genome sequencing and optical genome mapping were performed for three arRP cases homozygous for USH2A c.2276 G > T to exclude alternative genetic causes. A minigene splice assay was designed to investigate the effect of c.2276 G > T on pre-mRNA splicing, in presence or absence of the nearby c.2256 T > C variant. Moreover, an ush2a p.(Cys771Phe) zebrafish knock-in model mimicking human p.(Cys759Phe) was generated and characterized using functional and immunohistochemical analyses. Besides the homozygous c.2276 G > T USH2A variant, no alternative genetic causes were identified. Evaluation of the ush2a p.(Cys771Phe) zebrafish model revealed strongly reduced levels of usherin expression at the photoreceptor periciliary membrane, increased levels of rhodopsin localization in the photoreceptor cell body and decreased electroretinogram (ERG) b-wave amplitudes compared to wildtype controls. In conclusion, we confirmed pathogenicity of USH2A c.2276 G > T (p.(Cys759Phe)). Consequently, cases homozygous for c.2276 G > T can now receive a definite genetic diagnosis and can be considered eligible for receiving future QR-421a-mediated exon 13 skipping therapy.
(© 2022. The Author(s).)
Databáze: MEDLINE
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