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
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AB and ACA co-last authors.
Collaborators J Hou; C Klein; K Jedeon.
Contributors PMY, FdARN, AB and ACA designed the study. PMY, FdARN and ACA performed the mutation analysis of the Brazilian patients. PMY, DH, M-LF, SB and AB performed the RT-qPCR and immunofluorescence experiments. PMY, LCC, MCS, MEB, CD, JCF, RLF, PH, RVP and ACA followed all the patients and collected the data. All authors participated in the manuscript writing. PMY, FdARN, CB, MLDM, LCC, RVP, PH, CC, SB, AB and ACA revised the final manuscript.
Funding This work was supported by the grant CAPES/COFECUB (#733/2013) and by the French grant IDEX Sorbonne Paris Cité ‘Once upon a tooth’.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Comissão Nacional de Ética em Pesquisa (CONEP) (National Comittee for Ethics in Research).
Provenance and peer review Not commissioned; externally peer reviewed.
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