title: A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS.
abstract: Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Evelyne
authors.initials: E
authors.lastname: Huynh Cong
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Albane A
authors.initials: AA
authors.lastname: Bizet
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Assistance Publique-Hôpitaux de Paris, Department of Pediatric Nephrology, Necker Hospital, Paris, France;
authors.forename: Olivia
authors.initials: O
authors.lastname: Boyer
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Woerner
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Emilie
authors.initials: E
authors.lastname: Filhol
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Christelle
authors.initials: C
authors.lastname: Arrondel
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Flora
authors.initials: F
authors.lastname: Silbermann
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Nephrology and Transplantation and Intensive Care Unit, Necker Hospital, Paris, France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Canaud
authors.affiliation: Department of Nephrology, University of Sfax, Hedi Chaker Hospital, Sfax, Tunisia;
authors.forename: Jamil
authors.initials: J
authors.lastname: Hachicha
authors.affiliation: Department of Nephrology, Faculty of Medicine, Monastir, Tunisia;
authors.forename: Nasr
authors.initials: N
authors.lastname: Ben Dhia
authors.affiliation: INSERM U940, Paris Diderot University and Nephrology Unit, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Peraldi
authors.affiliation: Faculty of Medicine, Military Hospital of Tunis, Tunis, Tunisia;
authors.forename: Kais
authors.initials: K
authors.lastname: Harzallah
authors.affiliation: Department of Nephrology-Dialysis, Army Central Hospital, Kouba, Alger, Algeria;
authors.forename: Daouia
authors.initials: D
authors.lastname: Iftene
authors.affiliation: Assistance Publique-Hôpitaux de Marseille, Department of Pathology, la Timone Hospital, Marseille, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Daniel
authors.affiliation: INSERM U844, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier, France;
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Willems
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Nephrology and Transplantation and Intensive Care Unit, Necker Hospital, Paris, France;
authors.forename: Laure-Hélène
authors.initials: LH
authors.lastname: Noel
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Imagine Institute, Genomic Core Facility, Paris, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Paris-Descartes Sorbonne Paris-Cité University, Bioinformatics Core Facility, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mollet
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.affiliation: INSERM U1163, Laboratory of Hereditary Kidney Diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Assistance Publique-Hôpitaux de Paris, Department of Genetics, Necker Hospital, Paris, France; corinne.antignac@inserm.fr.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D002461:Cell Line, Transformed; D002648:Child; D002923:Cilia / Q000473:pathology / Q000502:physiology*; D005192:Family Health; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D050199:Podocytes / Q000473:pathology / Q000502:physiology*; D022502:Stress Fibers / Q000473:pathology / Q000502:physiology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008869:Microtubule-Associated Proteins; C000594121:TTC21B protein, human
keywords: focal segmental glomerulosclerosis; genetic renal disease; nephronophthisis; podocyte