Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

Author:

Dupont Marie Alice12,Humbert Camille12,Huber Céline342,Siour Quentin342,Guerrera Ida Chiara5,Jung Vincent5,Christensen Anni6,Pouliet Aurore7,Garfa-Traoré Meriem8,Nitschké Patrick29,Injeyan Marie10,Millar Kathryn10,Chitayat David1011,Shannon Patrick12,Girisha Katta Mohan13,Shukla Anju13,Mechler Charlotte14,Lorentzen Esben6,Benmerah Alexandre12,Cormier-Daire Valérie342,Jeanpierre Cécile12,Saunier Sophie12,Delous Marion12

Affiliation:

1. Laboratory of Hereditary Kidney Diseases, INSERM, Paris, France

2. Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France

3. Laboratory of Molecular and Physiopathological bases of osteochondrodysplasia, INSERM, Paris, France

4. Department of Genetics, Reference Centre for Skeletal Dysplasia, Assistance Publique - Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France

5. Proteomics Platform 3P5-Necker, Paris Descartes-Sorbonne Paris Cité University, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Paris, France

6. Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany

7. Genomics Core Facility, Imagine Institute and Structure Fédérative de Recherche Necker, INSERM UMR1163 and INSERM US24/CNRS UMS3633, Paris Descartes-Sorbonne Paris Cité University, Paris, France

8. Cell Imaging Platform UMS 24, Structure Fédérative de Recherche Necker, Inserm US24/CNRS UMS3633, Paris, France

9. Bioinformatics Core Facility, Paris Descartes-Sorbonne Paris Cité University, Paris, France

10. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

11. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

12. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

13. Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India

14. Assistance Publique - Hôpitaux de Paris, Louis Mourier Hospital, Colombes, France

Abstract

Abstract Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536–539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52−/− cells. Altogether, our findings allow a better comprehensive genotype–phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.

Funder

European Union’s Seventh Framework Programme

Novo Nordisk Foundation

Fondation pour la Recherche Médicale

Agence Nationale de la Recherche

Publisher

Oxford University Press (OUP)

Subject

Genetics(clinical),Genetics,Molecular Biology,General Medicine

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