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Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations
  1. Paulo Marcio Yamaguti1,2,
  2. Francisco de Assis Rocha Neves3,
  3. Dominique Hotton4,
  4. Claire Bardet5,
  5. Muriel de La Dure-Molla6,7,
  6. Luiz Claudio Castro8,
  7. Maria do Carmo Scher9,
  8. Maristela Estevão Barbosa10,
  9. Christophe Ditsch11,
  10. Jean-Christophe Fricain12,
  11. Renaud de La Faille13,
  12. Marie-Lucile Figueres14,
  13. Rosa Vargas-Poussou15,
  14. Pascal Houiller14,15,
  15. Catherine Chaussain5,15,
  16. Sylvie Babajko4,
  17. Ariane Berdal4,7,
  18. Ana Carolina Acevedo1,2
    1. 1Faculty of Health Sciences, Division of Dentistry, Oral Care Center for Inherited Diseases, University Hospital of Brasilia, University of Brasilia, Brasilia, Brazil
    2. 2Faculty of Health Sciences, Laboratory of Oral Histopathology, University of Brasilia, Brasilia, Brazil
    3. 3Faculty of Health Sciences, Laboratory of Molecular Pharmacology, University of Brasilia, Brasilia, Brazil
    4. 4Centre de Recherche des Cordeliers, University Paris-Diderot, INSERM UMR_S1138, Equipe Physiopathologie Orale Moléculaire, Paris, France
    5. 5EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School, University Paris Descartes, Sorbonne Paris Cité, Paris, France
    6. 6INSERM UMR_S1163, Bases moléculaires et physiopathologiques des ostéochondrodysplasies, Institut Imagine, Necker, Paris, France
    7. 7AP-HP, Referral Center for Rare Buccal and Facial Dysmorphologies CRMR MAFACE, Hôpital Rothschild, Paris, France
    8. 8Unit of Pediatric Endocrinology, University Hospital of Brasilia, Brasilia, Brazil
    9. 9Unit of Pediatric Nephrology, University Hospital of Brasilia, Brasilia, Brazil
    10. 10Unit of Pediatric Endocrinology, Hospital Materno Infantil de Brasilia, Brasilia, Brazil
    11. 11Centre Hospitalier de Dieppe, Dieppe, France
    12. 12CHU Bordeaux, Dental school, U1026 Tissue Bioengineering, University of Bordeaux/Inserm, Bordeaux, France
    13. 13Department of Nephrology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    14. 14Sorbonne 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
    15. 15AP-HP, Department of Genetics, Reference Center of Children and Adult Renal Hereditary Diseases (MARHEA), Hôpital European Georges Pompidou, Paris, France
    1. Correspondence to Dr Ana Carolina Acevedo; University of Brasilia, University Hospital of Brasilia, Oral Center for Inherited Diseases, Brasilia CEP:70372-050, Brazil; acevpoppe{at}gmail.com

    Abstract

    Background 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.

    Methods 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.

    Results 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.

    Conclusions 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.

    • Amelogenesis Imperfecta
    • Cldn19 protein
    • Hypomagnesemia 5, Renal, with Ocular Involvement
    • Amelogenesis

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