دورية أكاديمية
Scrutinizing pathogenicity of the USH2A c.2276 G > T; p.(Cys759Phe) variant.
| العنوان: | Scrutinizing pathogenicity of the USH2A c.2276 G > T; p.(Cys759Phe) variant. |
|---|---|
| المؤلفون: | 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. |
| المصدر: | NPJ genomic medicine [NPJ Genom Med] 2022 Jun 07; Vol. 7 (1), pp. 37. Date of Electronic Publication: 2022 Jun 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Nature in partnership with the Center of Excellence in Genomic Medicine Research at King Abdulaziz University Country of Publication: England NLM ID: 101685193 Publication Model: Electronic Cited Medium: Internet ISSN: 2056-7944 (Electronic) Linking ISSN: 20567944 NLM ISO Abbreviation: NPJ Genom Med Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Publication: 2016- : [London] : Springer Nature in partnership with the Center of Excellence in Genomic Medicine Research at King Abdulaziz University Original Publication: [London] : Nature Publishing Group, published in partnership with Center of Excellence in Genomic Medicine Research, [2016]- |
| مستخلص: | 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).) |
| References: | Mol Ther. 2021 Aug 4;29(8):2441-2455. (PMID: 33895329) Nucleic Acids Res. 1987 Sep 11;15(17):7155-74. (PMID: 3658675) J Comput Biol. 2004;11(2-3):377-94. (PMID: 15285897) Nature. 2020 May;581(7809):434-443. (PMID: 32461654) J Mol Graph. 1990 Mar;8(1):52-6, 29. (PMID: 2268628) Proc Natl Acad Sci U S A. 2020 Apr 21;117(16):9001-9012. (PMID: 32265282) Exp Eye Res. 2018 Aug;173:148-159. (PMID: 29777677) Brain. 2016 Apr;139(Pt 4):1123-35. (PMID: 26912635) J Clin Invest. 2010 Jun;120(6):1812-23. (PMID: 20440071) Sci Rep. 2018 Jun 26;8(1):9675. (PMID: 29946172) Exp Eye Res. 2020 Dec;201:108330. (PMID: 33121974) Sci Rep. 2018 Nov 26;8(1):17348. (PMID: 30478432) J Med Genet. 2003 Jan;40(1):e8. (PMID: 12525556) Am J Hum Genet. 2000 Jun;66(6):1975-8. (PMID: 10775529) Database (Oxford). 2017 Jan 1;2017:. (PMID: 28605766) Cell Rep. 2018 Oct 30;25(5):1268-1280.e4. (PMID: 30380417) Vision Res. 2007 Mar;47(5):624-33. (PMID: 17267005) Sci Rep. 2021 Jan 15;11(1):1526. (PMID: 33452396) Elife. 2016 Mar 07;5:e11613. (PMID: 26949250) Ophthalmology. 2017 Sep;124(9):1314-1331. (PMID: 28559085) Bioinformatics. 2014 May 15;30(10):1473-5. (PMID: 24463181) Eur J Hum Genet. 2004 May;12(5):407-10. (PMID: 14970843) Hum Mol Genet. 2020 Jul 21;29(11):1882-1899. (PMID: 31998945) Cell. 2019 Jan 24;176(3):535-548.e24. (PMID: 30661751) Hum Genet. 2018 Oct;137(10):779-794. (PMID: 30242501) Dev Dyn. 1995 Jul;203(3):253-310. (PMID: 8589427) Am J Hum Genet. 2021 Aug 5;108(8):1409-1422. (PMID: 34237280) Am J Hum Genet. 2021 Aug 5;108(8):1423-1435. (PMID: 34237281) Proteins. 2002 May 15;47(3):393-402. (PMID: 11948792) Ophthalmology. 2016 Jun;123(6):1375-85. (PMID: 26976702) Nucleic Acids Res. 2001 Mar 1;29(5):1185-90. (PMID: 11222768) J Comput Biol. 1997 Fall;4(3):311-23. (PMID: 9278062) Development. 2019 Sep 19;146(18):. (PMID: 31488567) Science. 2008 Apr 25;320(5875):524-7. (PMID: 18440926) Ophthalmology. 2016 May;123(5):1151-60. (PMID: 26927203) Matrix Biol. 2017 Jan;57-58:204-212. (PMID: 27425256) Zebrafish. 2018 Dec;15(6):597-609. (PMID: 30281416) J Med Genet. 2022 May;59(5):438-444. (PMID: 33910932) Genet Med. 2019 Aug;21(8):1751-1760. (PMID: 30643219) Ophthalmic Genet. 2018 Apr;39(2):291-292. (PMID: 29283788) Int J Mol Sci. 2021 Aug 30;22(17):. (PMID: 34502338) Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067. (PMID: 29165669) Proc Natl Acad Sci U S A. 1998 May 26;95(11):5857-64. (PMID: 9600884) Exp Eye Res. 2004 Aug;79(2):167-73. (PMID: 15325563) Otol Neurotol. 2019 Jan;40(1):121-129. (PMID: 30531642) Am J Med Genet A. 2015 Jul;167(7):1597-600. (PMID: 25823529) |
| معلومات مُعتمدة: | 1129 Velux Stiftung (Velux Foundation); 1129 Velux Stiftung (Velux Foundation); 1129 Velux Stiftung (Velux Foundation); 1129 Velux Stiftung (Velux Foundation) |
| تواريخ الأحداث: | Date Created: 20220607 Latest Revision: 20220716 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9174243 |
| DOI: | 10.1038/s41525-022-00306-z |
| PMID: | 35672333 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 2056-7944 |
|---|---|
| DOI: | 10.1038/s41525-022-00306-z |