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Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

Author

Listed:
  • Albane A. Bizet

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

  • Anita Becker-Heck

    (Novartis Institutes for Biomedical Research)

  • Rebecca Ryan

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

  • Kristina Weber

    (Max-Planck-Institute of Biochemistry)

  • Emilie Filhol

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

  • Pauline Krug

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

  • Jan Halbritter

    (Boston Children’s Hospital and Harvard Medical School
    University Clinic Leipzig)

  • Marion Delous

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

  • Marie-Christine Lasbennes

    (Novartis Institutes for Biomedical Research)

  • Bolan Linghu

    (Novartis Institutes for Biomedical Research)

  • Edward J. Oakeley

    (Novartis Institutes for Biomedical Research)

  • Mohammed Zarhrate

    (Paris Descartes Sorbonne Paris Cité University, Imagine Institute
    Inserm UMR-1163, Genomic Core Facility)

  • Patrick Nitschké

    (Paris Descartes Sorbonne Paris Cité University, Imagine Institute
    Paris Descartes Sorbonne Paris Cité University, Bioinformatics Core Facility)

  • Meriem Garfa-Traore

    (Cell Imaging Platform, INSERM US24 Structure Fédérative de recherche Necker, Paris Descartes Sorbonne Paris Cité University)

  • Fabrizio Serluca

    (Novartis Institutes for Biomedical Research)

  • Fan Yang

    (Novartis Institutes for Biomedical Research)

  • Tewis Bouwmeester

    (Novartis Institutes for Biomedical Research)

  • Lucile Pinson

    (Arnaud de Villeneuve University Health Center)

  • Elisabeth Cassuto

    (L'Archet II Hospital, Nice University Health Center)

  • Philippe Dubot

    (William Morey Hospital)

  • Neveen A. Soliman Elshakhs

    (Center of Pediatric Nephrology and Transplantation, Cairo University, Egyptian Group for Orphan Renal Diseases)

  • José A. Sahel

    (INSERM U968, CNRS UMR 7210; Sorbonne Universités, Université Pierre et Marie Curie, UMR S968
    Sorbonne Universités, Université Pierre et Marie Curie, UMR S968
    Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM, Direction de l'Hospitalisation et de l'Organisation des Soins)

  • Rémi Salomon

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute
    Assistance Publique—Hôpitaux de Paris, Necker-Enfants Malades Hospital)

  • Iain A. Drummond

    (Massachusetts General Hospital
    Harvard Medical School)

  • Marie-Claire Gubler

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

  • Corinne Antignac

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute
    Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital)

  • Salahdine Chibout

    (Novartis Institutes for Biomedical Research)

  • Joseph D. Szustakowski

    (Novartis Institutes for Biomedical Research)

  • Friedhelm Hildebrandt

    (Boston Children’s Hospital and Harvard Medical School)

  • Esben Lorentzen

    (Max-Planck-Institute of Biochemistry)

  • Andreas W. Sailer

    (Novartis Institutes for Biomedical Research)

  • Alexandre Benmerah

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

  • Pierre Saint-Mezard

    (Novartis Institutes for Biomedical Research)

  • Sophie Saunier

    (Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
    Paris Descartes Sorbonne Paris Cité University, Imagine Institute)

Abstract

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.

Suggested Citation

  • Albane A. Bizet & Anita Becker-Heck & Rebecca Ryan & Kristina Weber & Emilie Filhol & Pauline Krug & Jan Halbritter & Marion Delous & Marie-Christine Lasbennes & Bolan Linghu & Edward J. Oakeley & Moh, 2015. "Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9666
    DOI: 10.1038/ncomms9666
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