title: Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.
abstract: Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients.
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bardet
authors.affiliation: Department of Odontology, AP-HP, and Reference Center for Rare Diseases of the Metabolism of Calcium and Phosphorus, Nord Val de Seine Hospital, Bretonneau, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Courson
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.|Department of Oral and Cranio-maxillofacial Science, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.
authors.forename: Mayssam
authors.initials: M
authors.lastname: Khaddam
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.|Department of Odontology, AP-HP, and Reference Center for Rare Diseases of the Metabolism of Calcium and Phosphorus, Nord Val de Seine Hospital, Bretonneau, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Salmon
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Ribes
authors.affiliation: Department of Pediatric Nephrology, Charité University School of Medicine, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Thumfart
authors.affiliation: Division of Dentistry, Oral Care Center for Inherited Diseases, University Hospital of Brasilia, Faculty of Health Sciences, University of Brasilia (UnB), Brasilia, Brazil.
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Yamaguti
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.
authors.forename: Gael Y
authors.initials: GY
authors.lastname: Rochefort
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris-Diderot, Pierre et Marie Curie and Paris Descartes Universities, CNRS ERL 8228, Paris, France.
authors.forename: Marie-Lucile
authors.initials: ML
authors.lastname: Figueres
authors.affiliation: Department of Pediatric Nephrology, Charité University School of Medicine, Berlin, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Breiderhoff
authors.affiliation: Department of Genetics, AP-HP, and Reference Center of Children and Adult Renal Hereditary Diseases (MARHEA), European Hospital Georges Pompidou, Paris, France.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Garcia-Castaño
authors.affiliation: Laboratory CRRET, Paris-Est University, CNRS, Créteil, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Vallée
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Le Denmat
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Baroukh
authors.affiliation: Cochin Institute, Plate-Forme d'Imagerie Photonique, INSERM U1016, CNRS UMR8104, Paris Descartes University Sorbonne Paris Cité, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Guilbert
authors.affiliation: Cochin Institute, Transmission Electron Microscopy Platform, INSERM U1016, CNRS UMR8104, Paris Descartes University Sorbonne Paris Cité, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Cochin Institute, Transmission Electron Microscopy Platform, INSERM U1016, CNRS UMR8104, Paris Descartes University Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Massé
authors.affiliation: Laboratoire de Physique des Solides, CNRS, Paris Sud University, Orsay, and LCMCP-UPMC, Collège de France, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bazin
authors.affiliation: Fraunhofer Institute for Mechanics of Materials IWM, Halle, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Lorenz
authors.affiliation: Fraunhofer Institute for Mechanics of Materials IWM, Halle, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Morawietz
authors.affiliation: Division of Renal Diseases, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jianghui
authors.initials: J
authors.lastname: Hou
authors.affiliation: Human Anatomy and Embryology, Health University of Barcelona Campus-Bellvitge, University of Barcelona, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Carvalho-Lobato
authors.affiliation: Human Anatomy and Embryology, Health University of Barcelona Campus-Bellvitge, University of Barcelona, Barcelona, Spain.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Manzanares
authors.affiliation: CHU Bordeaux, Dental School, U1026 Tissue Bioengineering, University of Bordeaux/Inserm, Bordeaux, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Fricain
authors.affiliation: Department of Pediatrics, Centre Hospitalier Régional (CHR) d'Orléans, Orleans, France.
authors.forename: Deborah
authors.initials: D
authors.lastname: Talmud
authors.affiliation: GHPSO, Creil, France.
authors.forename: Renato
authors.initials: R
authors.lastname: Demontis
authors.affiliation: Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasilia (UNB), Brasilia, Brazil.
authors.forename: Francisco
authors.initials: F
authors.lastname: Neves
authors.affiliation: Department of Pediatric Endocrinology, AP-HP, Paris Diderot University, Robert Debré Hospital, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Zenaty
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris-Diderot, Pierre et Marie Curie and Paris Descartes Universities, CNRS ERL 8228, Paris, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Berdal
authors.affiliation: Fraunhofer Institute for Mechanics of Materials IWM, Halle, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kiesow
authors.affiliation: Fraunhofer Institute for Mechanics of Materials IWM, Halle, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Petzold
authors.affiliation: Laboratory CRRET, Paris-Est University, CNRS, Créteil, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Menashi
authors.affiliation: Department of Pediatric Endocrinology, AP-HP, Paris Sud University, School of Medicine, and Reference Center for Rare Diseases of the Metabolism of Calcium and Phosphorus, Paris, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Linglart
authors.affiliation: Division of Dentistry, Oral Care Center for Inherited Diseases, University Hospital of Brasilia, Faculty of Health Sciences, University of Brasilia (UnB), Brasilia, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Acevedo
authors.affiliation: Department of Genetics, AP-HP, and Reference Center of Children and Adult Renal Hereditary Diseases (MARHEA), European Hospital Georges Pompidou, Paris, France.
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
authors.affiliation: Department of Pediatric Nephrology, Charité University School of Medicine, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, Paris-Diderot, Pierre et Marie Curie and Paris Descartes Universities, CNRS ERL 8228, Paris, France.|Department of Physiology, AP-HP, and Reference Center of Children and Adult Renal Hereditary Diseases (MARHEA), Georges Pompidou European Hospital, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.|Department of Odontology, AP-HP, and Reference Center for Rare Diseases of the Metabolism of Calcium and Phosphorus, Nord Val de Seine Hospital, Bretonneau, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chaussain
mesh_terms: D000328:Adult; D000565:Ameloblasts / Q000378:metabolism* / Q000473:pathology; D000567:Amelogenesis Imperfecta / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002648:Child; D057167:Claudins / Q000172:deficiency* / Q000235:genetics; D003743:Dental Enamel / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D013577:Syndrome; D019108:Tight Junctions / Q000378:metabolism*; D055815:Young Adult
chemical_list: D057167:Claudins; C502010:claudin 16
keywords: AMELOGENESIS IMPERFECTA (AI); FAMILIAL HYPOMAGNESEMIA WITH HYPERCALCIURIA AND NEPHROCALCINOSIS (FHHNC); MMP-20; SECRETORY AMELOBLASTS; pH