Deficiency in <em>Gna11</em> impairs enamel mineralization by delaying ameloblast transition to the maturation stage in Familial Hypocalciuric Hypercalcemia type 2 — ASN Events
  1. Schedule
  2. CaSR-5 Session 11: CaSR: GIT and CNS
  3. Deficiency in Gna11 impairs enamel mineralization by delaying ameloblast transition to the maturation stage in Familial Hypocalciuric Hypercalcemia type 2

Deficiency in Gna11 impairs enamel mineralization by delaying ameloblast transition to the maturation stage in Familial Hypocalciuric Hypercalcemia type 2 (#266)

Franceska Kovaci 1 , Amina Attia 1 2 , Anne-Laure Lakhel 1 3 , Stefano Collins 1 4 , Nicolas Obtel 1 3 , Thibaud Coradin 1 4 , Fadil Hannan 5 , Rajesh Thakker 6 , Jean-Philippe Bertocchio 2 , Catherine Chaussain 1 3
  1. Université Paris Cité, Inserm UMR1333 Santé Orale, Paris, France
  2. Pathologies thyroïdiennes et tumorales endocrines, CCMR calcium-phosphate (réeau OSCAR) Hôpital Pitié-Salpêtrière, APHP, Paris, France
  3. Médecine bucco-dentaire, Hôpitaux Universitaires Bretonneau, APHP (CRMR calcium-phosphate, filière OSCAR et ERN Bond), Paris, France
  4. Sorbonne Université, CNRS, Laboratoire de Chimie de la Matière Condensée de Paris, Paris, France
  5. Nuffield Department of Women&Reproductive Health, University of Oxford, Oxford, UK
  6. Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford- NIHR Oxford Biomedical Research Centre-Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Familial hypocalciuric hypercalcemia (FHH) is a rare genetic disorder caused by inactivating mutations of the genes CASR (FHH type 1), GNA11 (FHH type 2), or AP2S1 (FHH type 3), that play critical roles in the extracellular calcium-sensing pathway. FHH is characterized by PTH-depended hypercalcemia in serum, and reduced urinary calcium excretion. We recently reported that FHH patients exhibit dental enamel abnormalities, particularly severe in FHH type 2 patients. However, the mechanisms by which chronic hypercalcemia and Gna11 deficiency may influence enamel formation remain poorly understood.

To address these questions, we are analyzing the Gna11-Tm1b mouse model representing FHH type 2. We hypothesize that this model recapitulates the dental enamel phenotype observed in patients. Our aims are to characterize the dental enamel phenotype, and elucidate the cellular and molecular mechanisms by which FHH type 2 inactivating variants alter enamel formation.

To characterize the dental phenotype, we performed Micro-CT analysis of incisors and molars in Gna11-Tm1b mice. Heterozygous Gna11-Tm1b+/- mutant mice showed significantly reduced enamel volume and density in both incisors and molars compared to Gna11-Tm1b+/+ control mice at 2 months of age. Histological analyses revealed more retention of enamel matrix proteins during the maturation stage of ameloblasts in mutant compared to control mice. Consistently, immunofluorescence demonstrated persistent amelogenin protein accumulation during maturation stage in mutant mice. Furthermore, while ameloblastin expression was restricted to the transition stage of ameloblasts in control mice, it persisted into maturation in mutant mice. In addition, the expression of tight junction marker Claudin-10 was similarly detected until the transition stage in the dental epithelium in control mice, whereas in mutant it persisted until the maturation stage. In conclusion, these results suggest that the dental epithelium in mutant mice exhibits a delayed or incomplete transition from the secretory to the maturation stage, impairing enamel matrix clearance and mineralization.