Suzanne de Bruijn

184 Chapter 4 YPEL2 in NL-SV1. Importantly, qPCR provided evidence for the increased expression of the retinal enhancer in UK-SV2 ROs, with TF binding sites for NRL which is preferentially expressed in rod photoreceptors, the primary cell type affected in RP. Although increased expression of SMG8 , YPEL2 , or the retinal enhancer cannot be excluded from contributing to the phenotype in individual families, these experimental data support the hypothesis of a convergent mechanism of GDPD1 entry into the active neo-TAD with retinal enhancers for all eight complex RP17-SVs. This is further supported by the observation that the two affected individuals in family UK13 with an earlier age of onset and more severe phenotype, compared to all other families, have a triplication (UK-SV6) where two copies of GDPD1 are predicted to enter the active neo-TAD. Our data implicate increased retinal expression of GDPD1 as a dominant gain-of- function mechanism leading to adRP. GDPD1 encodes a glycerophosphodiesterase, that can hydrolyze lysophosphatidylcholine (lyso-PC) to lysophosphatidic acid (LPA) 39 with lysophospholipase D (lysoPLD) activity on various lysophospholipids. 40 GPDP1 is detected at low expression in the healthy retina, therefore, increased expression of GDPD1 could lead to dysregulation of lipid metabolism, which is known to be critical for photoreceptor function although the exact mechanisms of photoreceptor cell death are not known. 41,42,43 Disruption of lipid metabolism leading to adRP, combined with the adult age of onset, opens avenues for therapeutic intervention to preserve vision by restoring lipid homeostasis. ACKNOWLEDGEMENTS We thank the affected individuals and their families for participating in this study and our funding bodies. We thank Saskia D. van de Velde-Visser for cell culture work, Marijke N. Zonneveld-Vrieling, Mubeen Khan, Rolph Pfundt, M. Imran Khan, for experimental contributions, Alex Hoischen for expert contribution, Galuh Dyah Nur Astuti for bioinformatics support, Edward Bloch for taking skin biopsies and Karin W. Littink, Suzanne IJzer, Irma Lopez, Anneke I. den Hollander and Samantha Malka for their effort in sample collection. This research was supported by grants from Retina UK, Fight for Sight (UK), Moorfields Eye Charity (UK), the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust, UCL Institute of Ophthalmology, GOSH and Cambridge (UK), and The Wellcome Trust. The study was also financially supported by DCN Radboudumc grant (to FPMC and HK), the Foundation Fighting Blindness (PPA-0517-0717-RAD, to SR and FPMC), and the Rotterdamse Stichting Blindenbelangen, the Stichting Blindenhulp, the