Year: 2026
Type: review
Abstract: Pathogenic variants in RP2 cause X‐linked RP2 ‐associated retinopathy, a rare inherited retinal disorder typically characterized by childhood onset and progression to severe visual impairment within the first three decades of life. Despite its clinical severity, comprehensive clinical and genetic data on RP2 ‐associated retinopathy remain limited and no therapeutic approaches have yet progressed toward clinical application. Here, we provide an overview of current molecular, clinical, and therapeutic knowledge on RP2 ‐associated retinopathy together with an analysis of the spectrum and distribution of clinically classified, ClinVar‐curated variants. Analysis of 325 ACMG/AMP Class 3–5 variants revealed that among pathogenic and likely pathogenic variants, frameshift and nonsense variants predominated, supporting loss of RP2 function as the major disease mechanism as previously described. In contrast, variants of uncertain significance were largely missense variants, underscoring the particular challenge of missense variant interpretation in RP2. Exon distribution of RP2 variants did not deviate from expectation for Class 3 variants, or for Class 4 and 5 variants in exons 2–4. However, we observed a significant enrichment of Class 4/5 variants in exon 1, driven mainly by initiator codon variants, and a depletion of Class 4/5 variants in exon 5. By integrating published knowledge on molecular mechanisms, genetic variants, clinical progression, and therapeutic development, with a detailed analysis of ClinVar‐annotated RP2 variants, this narrative review outlines the current understanding of RP2 ‐associated retinopathy and identifies key gaps that will need to be addressed for therapeutic development and clinical translation. Trial Registration : ClinicalTrials.gov: NCT06982417
Source: Human Mutation
DOI: 10.1155/humu/1839164
Authors: Nina Bögershausen, Patricia Döring, Maximilian Gerhardt, Alisa Fedorenko, Carolin Strohmeyer, Rozhin Bayati, Yun Li, Gökhan Yigit, Emrah Kaygusuz, Oscar Gutiérrez-Gutiérrez, Marianne Gaubert, Behnam Javanmardi, Karin Boss, Antonia Kowallick, Peter Krawitz, Stylianos Michalakis, Marius Ueffing, Wolfram-Hubertus Zimmermann, Hans Hoerauf, Hildegard Büning, Nicolas Feltgen, Lukas Cyganek, Bernd Wollnik
Institutions: Universitätsmedizin Göttingen, University of Göttingen, LMU Klinikum, Ludwig-Maximilians-Universität München, Bilecik Şeyh Edebali Üniversitesi, University Hospital Bonn, Universitätsklinikum Tübingen, Fraunhofer Institute for Translational Medicine and Pharmacology, German Centre for Cardiovascular Research, Multiscale Bioimaging, Else Kröner Fresenius Center for Optogenetic Therapies, Medizinische Hochschule Hannover, University Hospital of Basel
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,740
OpenAlex ID: W7222826752