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

Marie Alice Dupont, Camille Humbert, Céline Huber, Quentin Siour, Ida Chiara Guerrera, Vincent Jung, Anni Christensen, Aurore Pouliet, Meriem Garfa-Traoré, Patrick Nitschké, Marie Injeyan, Kathryn Millar, David Chitayat, Patrick Shannon, Katta Mohan Girisha, Anju Shukla, Charlotte Mechler, Esben Lorentzen, Alexandre Benmerah, Valérie Cormier-DaireCécile Jeanpierre, Sophie Saunier, Marion Delous

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2720-2737
Number of pages18
JournalHuman Molecular Genetics
Issue number16
Publication statusPublished - 15-08-2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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