de Nys, R.van Eyk, C.L.Ritchie, T.Møller, R.S.Scheffer, I.E.Marini, C.Bhattacharjee, R.Kumar, R.Gecz, J.2024-02-092024-02-092024Translational Psychiatry, 2024; 14(1):1-92158-31882158-3188https://hdl.handle.net/2440/140414Clustering Epilepsy (CE) is an epileptic disorder with neurological comorbidities caused by heterozygous variants of the X chromosome gene Protocadherin 19 (PCDH19). Recent studies have implicated dysregulation of the Nuclear Hormone Receptor (NHR) pathway in CE pathogenesis. To obtain a comprehensive overview of the impact and mechanisms of loss of PCDH19 function in CE pathogenesis, we have performed epigenomic, transcriptomic and proteomic analysis of CE relevant models. Our studies identified differential regulation and expression of Androgen Receptor (AR) and its targets in CE patient skin fibroblasts. Furthermore, our cell culture assays revealed the repression of PCDH19 expression mediated through ERα and the co-regulator FOXA1. We also identified a protein-protein interaction between PCDH19 and AR, expanding upon the intrinsic link between PCDH19 and the NHR pathway. Together, these results point to a novel mechanism of NHR signaling in the pathogenesis of CE that can be explored for potential therapeutic options.en© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http:// creativecommons.org/licenses/by/4.0/.CadherinsCluster AnalysisEpilepsyHumansMultiomicsProteomicsProtocadherinsMedical geneticsmolecular neurosciencepsychiatric disordersHumansEpilepsyCadherinsCluster AnalysisProteomicsProtocadherinsMultiomicsJournal article10.1038/s41398-024-02783-52024-02-05683092van Eyk, C.L. [0000-0003-0345-9944]Ritchie, T. [0000-0003-2951-6820]Bhattacharjee, R. [0000-0003-2740-6986]Kumar, R. [0000-0001-7976-8386]Gecz, J. [0000-0002-7884-6861]