N Obtel, A Le Cabec, A-L Lakhel, A Attia, C Andrique, F Hermans, F Kovaci, T N Nguyen, A Chansavang, A Percot, C Torrens, D Vangu, F Vaysse, M Gadion, F Savagner, T Edouard, A Bloch-Zupan, B Lukić, A Rack, A Brunelle, A Linglart, E Pasmant, F Ramirez Rozzi, F M Hannan, C Gaucher, T Coradin, R V Thakker, J-P Bertocchio, C Chaussain
Abnormal enamel mineralization has been reported in genetic conditions associated with hypocalcemia but never with hypercalcemia. In the present study, we report 10 patients from 2 unrelated families in whom hypomineralized enamel co-segregated with hypercalcemia due to a complete deletion or frameshifting premature truncation (p.(Ser18Argfs*2)) of the guanine nucleotide-binding protein (G-protein) subunit α11 (GNA11) gene. Both GNA11 variants were heterozygous and predicted to cause a loss of function of Gα11. Multiproxy imaging analyses of naturally exfoliated primary teeth and clinically extracted permanent teeth from 2 affected patients revealed abnormal enamel mineralization, with constitutive patches of hypomineralization following no set pattern. In parallel, the study of wild-type mouse tooth germs using combined molecular and protein analyses showed Gna11 and Gα11 protein expression in ameloblasts at the secretion and maturation stages, as well as in odontoblasts, suggesting a role for Gα11 in tooth formation. Furthermore, the analysis of a mouse model of Familial Hypocalciuric Hypercalcemia 2 (FHH2) revealed delayed onset of enamel mineralization in the continuously growing incisors and hypomineralized enamel in both incisor and molars of heterozygous (Gna11Tm1b+/-) mice, with defects that are very similar to those affecting human FHH2 teeth. In conclusion, our study reveals that abnormal enamel mineralization may occur in association with hypercalcemia due to loss-of-function GNA11 mutations, opening a new field of investigation and highlighting the need to include a dentist in the multidisciplinary team in charge of patients with monogenic calcium disorders.