[en] 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.
Christensen, Anni; Max-Planck-Institute of Biochemistry > 6Department of Structural Cell Biology
Pouliet, Aurore; Université Paris Descartes > Structure Fédérative de Recherche Necker > Plateforme Génomique
Garfa Traoré, Meriem; Université Paris Descartes > Structure Fédérative de Recherche Necker > Plateforme Imagerie
Nitschké, Patrick; Université Paris Descartes > Institut Imagine > Plateforme bio informatique
Injeyan, Marie; Mount Sinai Hospital, University of Toronto > Department of Obstetrics and Gynecology > The Prenatal Diagnosis and Medical Genetics Program
Millar, Kathryn; Mount Sinai Hospital, University of Toronto > Department of Obstetrics and Gynecology > The Prenatal Diagnosis and Medical Genetics Program
Chitayat, David; Mount Sinai Hospital, University of Toronto > Department of Obstetrics and Gynecology > The Prenatal Diagnosis and Medical Genetics Program
Shannon, Patrick; Mount Sinai Hospital, University of Toronto > Department of Pathology and laboratory Medicine,
Girisha, Katta Mohan; Manipal Academy of Higher Education > Department of Medical Genetics, Kasturba Medical College,
Schukla, Hanju; Manipal Academy of Higher Education > Department of Medical Genetics
Mechler, Charlotte; AP HP > Hôpital Louis Mourier
Lorentzen, Esben; Max-Planck-Institute of Biochemistry > Department of Structural Cell Biology
Benmerah, Alexandre; Université Paris Descartes > Institut Imagine > Laboratoire des maladies rénales héréditaires
Cormier Daire, Valérie; Université Paris Descartes > Institut Imagine > Laboratory of Molecular and Physiopathological bases of osteochondrodysplasia
Jeanpierre, Cécile; Université Paris Descartes > Institut Imagine > Laboratoire des maladies rénales héréditaires
Saunier, Sophie; Université Paris Descartes > Institut Imagine > Laboratoire des maladies rénales héréditaires
Delous, Marion; Université Paris Descartes > Institut Imagine > Laboratoire des maladies rénales héréditaires
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