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

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  • Marie Alice Dupont, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Camille Humbert, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Céline Huber, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Quentin Siour, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Ida Chiara Guerrera, Proteomics Platform 3P5-Necker, Paris Descartes-Sorbonne Paris Cité University, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75015 Paris, France.
  • ,
  • Vincent Jung, Proteomics Platform 3P5-Necker, Paris Descartes-Sorbonne Paris Cité University, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75015 Paris, France.
  • ,
  • Anni Christensen
  • Aurore Pouliet, Genomics Core Facility, Imagine Institute and Structure Fédérative de Recherche Necker, INSERM UMR1163 and INSERM US24/CNRS UMS3633, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France.
  • ,
  • Meriem Garfa-Traore, Cell Imaging Platform UMS 24, Structure Fédérative de Recherche Necker, Inserm US24/CNRS UMS3633, 75015 Paris, France.
  • ,
  • Patrick Nitschké, Bioinformatics Core Facility, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France.
  • ,
  • Marie Injeyan, The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • ,
  • Kathryn Millar, The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • ,
  • David Chitayat, Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • ,
  • Patrick Shannon, Department of Pathology and laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • ,
  • Katta Mohan Girisha, Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  • ,
  • Anju Shukla, Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  • ,
  • Charlotte Mechler, AP-HP, Louis Mourier Hospital, 92701 Colombes, France.
  • ,
  • Esben Lorentzen
  • Alexandre Benmerah, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Valérie Cormier-Daire, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Cécile Jeanpierre, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Sophie Saunier, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • ,
  • Marion Delous, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.

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) 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-localised 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 amongst IFT52-related cases and revealed a novel, extra-ciliary role for IFT52 which disruption may contribute to pathophysiological mechanisms.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind28
Nummer16
Sider (fra-til)2720-2737
Antal sider18
ISSN0964-6906
DOI
StatusUdgivet - 15 aug. 2019
Eksternt udgivetJa

Bibliografisk note

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