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

Author

Listed:
  • Roly Megaw

    (University of Edinburgh)

  • Hashem Abu-Arafeh

    (University of Edinburgh)

  • Melissa Jungnickel

    (University of Edinburgh)

  • Carla Mellough

    (Newcastle University)

  • Christine Gurniak

    (Universitat Bonn)

  • Walter Witke

    (Universitat Bonn)

  • Wei Zhang

    (UMASS Medical School)

  • Hemant Khanna

    (UMASS Medical School)

  • Pleasantine Mill

    (University of Edinburgh)

  • Baljean Dhillon

    (University of Edinburgh)

  • Alan F. Wright

    (University of Edinburgh)

  • Majlinda Lako

    (Newcastle University)

  • Charles ffrench-Constant

    (University of Edinburgh)

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.

Suggested Citation

  • Roly Megaw & Hashem Abu-Arafeh & Melissa Jungnickel & Carla Mellough & Christine Gurniak & Walter Witke & Wei Zhang & Hemant Khanna & Pleasantine Mill & Baljean Dhillon & Alan F. Wright & Majlinda Lak, 2017. "Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00111-8
    DOI: 10.1038/s41467-017-00111-8
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    Cited by:

    1. Roly Megaw & Abigail Moye & Zhixian Zhang & Fay Newton & Fraser McPhie & Laura C. Murphy & Lisa McKie & Feng He & Melissa K. Jungnickel & Alex Kriegsheim & Peter A. Tennant & Chloe Brotherton & Christ, 2024. "Ciliary tip actin dynamics regulate photoreceptor outer segment integrity," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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