title: Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations.
abstract: Amelogenesis imperfecta (AI) is a group of genetic diseases characterised by tooth enamel defects. AI was recently described in patients with familial hypercalciuria and hypomagnesaemia with nephrocalcinosis (FHHNC) caused by CLDN16 mutations. In the kidney, claudin-16 interacts with claudin-19 to control the paracellular passage of calcium and magnesium. FHHNC can be linked to mutations in both genes. Claudin-16 was shown to be expressed during amelogenesis; however, no data are available on claudin-19. Moreover, the enamel phenotype of patients with CLDN19 mutations has never been described. In this study, we describe the clinical and genetic features of nine patients with FHHNC carrying CLDN19 mutations and the claudin-19 expression profile in rat ameloblasts.
  
  
  
  Six FHHNC Brazilian patients were subjected to mutational analysis. Three additional French patients were recruited for orodental characterisation. The expression profile of claudin-19 was evaluated by RT-qPCR and immunofluorescence using enamel epithelium from rat incisors.
  
  
  
  All patients presented AI at different degrees of severity. Two new likely pathogenic variations in CLDN19 were found: p.Arg200Gln and p.Leu90Arg. RT-qPCR revealed low Cldn19 expression in ameloblasts. Confocal analysis indicated that claudin-19 was immunolocalised at the distal poles of secretory and maturing ameloblasts.
  
  
  
  For the first time, it was demonstrated that AI is associated with FHHNC in patients carrying CLDN19 mutations. The data suggest claudin-19 as an additional determinant in enamel formation. Indeed, the coexistence of hypoplastic and hypomineralised AI in the patients was consistent with claudin-19 expression in both secretory and maturation stages. Additional indirect systemic effects cannot be excluded.
authors.affiliation: Faculty of Health Sciences, Division of Dentistry, Oral Care Center for Inherited Diseases, University Hospital of Brasilia, University of Brasilia, Brasilia, Brazil.|Faculty of Health Sciences, Laboratory of Oral Histopathology, University of Brasilia, Brasilia, Brazil.
authors.forename: Paulo Marcio
authors.identifier: 0000-0002-9366-3852
authors.initials: PM
authors.lastname: Yamaguti
authors.affiliation: Faculty of Health Sciences, Laboratory of Molecular Pharmacology, University of Brasilia, Brasilia, Brazil.
authors.forename: Francisco de Assis Rocha
authors.initials: FA
authors.lastname: Neves
authors.affiliation: Centre de Recherche des Cordeliers, University Paris-Diderot, INSERM UMR_S1138, Equipe Physiopathologie Orale Moléculaire, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Hotton
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School, University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bardet
authors.affiliation: INSERM UMR_S1163, Bases moléculaires et physiopathologiques des ostéochondrodysplasies, Institut Imagine, Necker, Paris, France.|AP-HP, Referral Center for Rare Buccal and Facial Dysmorphologies CRMR MAFACE, Hôpital Rothschild, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: de La Dure-Molla
authors.affiliation: Unit of Pediatric Endocrinology, University Hospital of Brasilia, Brasilia, Brazil.
authors.forename: Luiz Claudio
authors.identifier: 0000-0002-9166-1837
authors.initials: LC
authors.lastname: Castro
authors.affiliation: Unit of Pediatric Nephrology, University Hospital of Brasilia, Brasilia, Brazil.
authors.forename: Maria do Carmo
authors.identifier: 0000-0002-7946-8313
authors.initials: MD
authors.lastname: Scher
authors.affiliation: Unit of Pediatric Endocrinology, Hospital Materno Infantil de Brasilia, Brasilia, Brazil.
authors.forename: Maristela Estevão
authors.identifier: 0000-0002-2729-8527
authors.initials: ME
authors.lastname: Barbosa
authors.affiliation: Centre Hospitalier de Dieppe, Dieppe, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Ditsch
authors.affiliation: CHU Bordeaux, Dental school, U1026 Tissue Bioengineering, University of Bordeaux/Inserm, Bordeaux, France.
authors.forename: Jean-Christophe
authors.identifier: 0000-0001-7855-6437
authors.initials: JC
authors.lastname: Fricain
authors.affiliation: Department of Nephrology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Renaud
authors.identifier: 0000-0001-5550-0684
authors.initials: R
authors.lastname: de La Faille
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, CNRS ERL_8228, Paris, France.
authors.forename: Marie-Lucile
authors.identifier: 0000-0002-1473-2064
authors.initials: ML
authors.lastname: Figueres
authors.affiliation: AP-HP, Department of Genetics, Reference Center of Children and Adult Renal Hereditary Diseases (MARHEA), Hôpital European Georges Pompidou, Paris, France.
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, CNRS ERL_8228, Paris, France.|AP-HP, Department of Genetics, Reference Center of Children and Adult Renal Hereditary Diseases (MARHEA), Hôpital European Georges Pompidou, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.affiliation: EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School, University Paris Descartes, Sorbonne Paris Cité, Paris, France.|AP-HP, Department of Genetics, Reference Center of Children and Adult Renal Hereditary Diseases (MARHEA), Hôpital European Georges Pompidou, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chaussain
authors.affiliation: Centre de Recherche des Cordeliers, University Paris-Diderot, INSERM UMR_S1138, Equipe Physiopathologie Orale Moléculaire, Paris, France.
authors.forename: Sylvie
authors.identifier: 0000-0001-9047-3490
authors.initials: S
authors.lastname: Babajko
authors.affiliation: Centre de Recherche des Cordeliers, University Paris-Diderot, INSERM UMR_S1138, Equipe Physiopathologie Orale Moléculaire, Paris, France.|AP-HP, Referral Center for Rare Buccal and Facial Dysmorphologies CRMR MAFACE, Hôpital Rothschild, Paris, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Berdal
authors.affiliation: Faculty of Health Sciences, Division of Dentistry, Oral Care Center for Inherited Diseases, University Hospital of Brasilia, University of Brasilia, Brasilia, Brazil.|Faculty of Health Sciences, Laboratory of Oral Histopathology, University of Brasilia, Brasilia, Brazil.
authors.forename: Ana Carolina
authors.identifier: 0000-0001-7110-7110
authors.initials: AC
authors.lastname: Acevedo
keywords: Amelogenesis; Amelogenesis Imperfecta; Cldn19 protein; Hypomagnesemia 5, Renal, with Ocular Involvement