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

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, Mohammed Zarhrate, Patrick Nitschké, Meriem Garfa-Traore, Fabrizio Serluca, Fan Yang, Tewis Bouwmeester, Lucile Pinson, Elisabeth Cassuto, Philippe Dubot, Neveen A. Soliman Elshakhs, José A. Sahel, Rémi Salomon, Iain A. Drummond, Marie-Claire Gubler, Corinne Antignac, Salahdine Chibout, Joseph D. Szustakowski, Friedhelm Hildebrandt, Esben Lorentzen, Andreas W. Sailer, Alexandre Benmerah, Pierre Saint-Mezard () and Sophie Saunier ()
Additional contact information
Albane A. Bizet: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
Anita Becker-Heck: Novartis Institutes for Biomedical Research
Rebecca Ryan: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
Kristina Weber: Max-Planck-Institute of Biochemistry
Emilie Filhol: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
Pauline Krug: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
Jan Halbritter: Boston Children’s Hospital and Harvard Medical School
Marion Delous: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
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
Patrick Nitschké: Paris Descartes Sorbonne Paris Cité University, Imagine Institute
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
Rémi Salomon: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
Iain A. Drummond: Massachusetts General Hospital
Marie-Claire Gubler: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
Corinne Antignac: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases
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
Pierre Saint-Mezard: Novartis Institutes for Biomedical Research
Sophie Saunier: Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9666

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