Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization.
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.
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Albane A
AA
Bizet
Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
Anita
A
Becker-Heck
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Rebecca
R
Ryan
Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Kristina
K
Weber
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Emilie
E
Filhol
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Pauline
P
Krug
Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Nephrology, Department of Internal Medicine, University Clinic Leipzig, 04103 Leipzig, Germany.
Jan
J
Halbritter
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Marion
M
Delous
Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
Marie-Christine
MC
Lasbennes
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Bolan
B
Linghu
Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
Edward J
EJ
Oakeley
Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.|Inserm UMR-1163, Genomic Core Facility, 75015 Paris, France.
Mohammed
M
Zarhrate
Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Bioinformatics Core Facility, 75015 Paris, France.
Patrick
P
Nitschké
Cell Imaging Platform, INSERM US24 Structure Fédérative de recherche Necker, Paris Descartes Sorbonne Paris Cité University, 75015 Paris, France.
Meriem
M
Garfa-Traore
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Fabrizio
F
Serluca
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Fan
F
Yang
Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
Tewis
T
Bouwmeester
Department of Medical Genetic, Arnaud de Villeneuve University Health Center, 34090 Montpellier, France.
Lucile
L
Pinson
Nephrology department, L'Archet II Hospital, Nice University Health Center, 06202 Nice, France.
Elisabeth
E
Cassuto
Hemodialysis-Nephrology Department, William Morey Hospital, 71321 Chalon-sur-Saône, France.
Philippe
http://orcid.org/0000-0002-1010-0107
P
Dubot
Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Cairo University, Egyptian Group for Orphan Renal Diseases, 11956 Cairo, Egypt.
Neveen A Soliman
NAS
Elshakhs
INSERM U968, CNRS UMR 7210; Sorbonne Universités, Université Pierre et Marie Curie, UMR S968, Institut de la vision, 75012 Paris, France.|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.
José A
JA
Sahel
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.|Assistance Publique-Hôpitaux de Paris, Pediatric Nephrologic department, Necker-Enfants Malades Hospital, 75015 Paris, France.
Rémi
R
Salomon
Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts 02114, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA.
Iain A
IA
Drummond
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Marie-Claire
MC
Gubler
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.|Assistance Publique-Hôpitaux de Paris, Department of Genetics, Necker-Enfants Malades Hospital, 75015 Paris, France.
Corinne
C
Antignac
Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
Salahdine
S
Chibout
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Joseph D
JD
Szustakowski
Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Friedhelm
F
Hildebrandt
Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Esben
E
Lorentzen
Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
Andreas W
AW
Sailer
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Alexandre
A
Benmerah
Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
Pierre
P
Saint-Mezard
Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.|Paris Descartes Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Sophie
S
Saunier
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016764:Cell Polarity / Q000235:genetics; D002942:Circular Dichroism; D004625:Embryo, Nonmammalian; D005260:Female; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047468:Immunoprecipitation; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008850:Microphthalmos / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D010375:Pedigree; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; C000601103:MAP4 protein, human; D008869:Microtubule-Associated Proteins; C412724:TRAF3IP1 protein, human; D029961:Zebrafish Proteins; C528684:traf3ip1 protein, zebrafish