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 language | English |
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Article number | 271 |
Number of pages | 10 |
Journal | Nature Communications |
Volume | 8 |
Issue number | 271 |
Early online date | 16 Aug 2017 |
DOIs | |
Publication status | E-pub ahead of print - 16 Aug 2017 |
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Profiles
-
Baljean Dhillon
- Deanery of Clinical Sciences - NES Personal Chair of Clinical Ophthalmology
- Centre for Clinical Brain Sciences
- Division of Health Sciences
- Ophthalmology
- Edinburgh Neuroscience
Person: Academic: Research Active
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Charles Ffrench-Constant
- Centre for Regenerative Medicine
- Anne Rowling Regenerative Neurology Clinic
- Edinburgh Neuroscience
- Deanery of Clinical Sciences - Visitor: Official Visitor
Person: Academic: Research Active , Affiliated Independent Researcher