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

Nat Commun. 2015 Oct 21;6:8666. doi: 10.1038/ncomms9666.

Albane A Bizet ¹ ², Anita Becker-Heck ³, Rebecca Ryan ¹ ², Kristina Weber ⁴, Emilie Filhol ¹ ², Pauline Krug ¹ ², Jan Halbritter ⁵ ⁶, Marion Delous ¹ ², Marie-Christine Lasbennes ³, Bolan Linghu ⁷, Edward J Oakeley ³, Mohammed Zarhrate ² ⁸, Patrick Nitschké ² ⁹, Meriem Garfa-Traore ¹⁰, Fabrizio Serluca ⁷, Fan Yang ⁷, Tewis Bouwmeester ³, Lucile Pinson ¹¹, Elisabeth Cassuto ¹², Philippe Dubot ¹³, Neveen A Soliman Elshakhs ¹⁴, José A Sahel ¹⁵ ¹⁶, Rémi Salomon ¹ ² ¹⁷, Iain A Drummond ¹⁸ ¹⁹, Marie-Claire Gubler ¹ ², Corinne Antignac ¹ ² ²⁰, Salahdine Chibout ³, Joseph D Szustakowski ⁷, Friedhelm Hildebrandt ⁵, Esben Lorentzen ⁴, Andreas W Sailer ³, Alexandre Benmerah ¹ ², Pierre Saint-Mezard ³, Sophie Saunier ¹ ²

Affiliations

1 Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.
2 Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
3 Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
4 Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
5 Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
6 Division of Nephrology, Department of Internal Medicine, University Clinic Leipzig, 04103 Leipzig, Germany.
7 Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
8 Inserm UMR-1163, Genomic Core Facility, 75015 Paris, France.
9 Paris Descartes Sorbonne Paris Cité University, Bioinformatics Core Facility, 75015 Paris, France.
10 Cell Imaging Platform, INSERM US24 Structure Fédérative de recherche Necker, Paris Descartes Sorbonne Paris Cité University, 75015 Paris, France.
11 Department of Medical Genetic, Arnaud de Villeneuve University Health Center, 34090 Montpellier, France.
12 Nephrology department, L'Archet II Hospital, Nice University Health Center, 06202 Nice, France.
13 Hemodialysis-Nephrology Department, William Morey Hospital, 71321 Chalon-sur-Saône, France.
14 Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Cairo University, Egyptian Group for Orphan Renal Diseases, 11956 Cairo, Egypt.
15 INSERM U968, CNRS UMR 7210; Sorbonne Universités, Université Pierre et Marie Curie, UMR S968, Institut de la vision, 75012 Paris, France.
16 Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM, Direction de l'Hospitalisation et de l'Organisation des Soins, Centre d'Investigation Clinique 1423, 75012 Paris, France.
17 Assistance Publique-Hôpitaux de Paris, Pediatric Nephrologic department, Necker-Enfants Malades Hospital, 75015 Paris, France.
18 Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts 02114, USA.
19 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA.
20 Assistance Publique-Hôpitaux de Paris, Department of Genetics, Necker-Enfants Malades Hospital, 75015 Paris, France.

PMID: 26487268 DOI: 10.1038/ncomms9666

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.

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