Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models

Roly Megaw, Hashem Abu-Arafeh, Melissa Jungnickel, Carla Mellough, Christine Gurniak-Witke, Walter Witke, Wei Zhang, Hemant Khanna, Pleasantine Mill, Baljean Dhillon, Alan F. Wright, Majlinda Lako, Charles Ffrench-Constant

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.
Original languageEnglish
Article number271
Number of pages10
JournalNature Communications
Volume8
Issue number271
Early online date16 Aug 2017
DOIs
Publication statusE-pub ahead of print - 16 Aug 2017

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