To mineralize and not to mineralize: the FAM20A-related rare disease paradox – MINERAR

The project is dedicated to a rare disease related to pathogenic FAM20A alleles. Enamel-Renal-Gingival syndrome (ERS) shows mineralization defects in tooth enamel and ectopic mineralization associated with soft tissue outgrowth, creating an extreme buccal handicap aside extraoral symptoms. There are no therapeutic option, except mutilating surgeries in adult mouth. Mechanisms of the malformative process and ectopic mineralization in ERS are undefined and biomarkers lack today. Partners 1 and 2 manage a representative ERS patient cohort, its annotated biobank and the animal model. Their preliminary data suggest that ERS progression is due to a pathogenic secretome of diseased cells, including enamel protein amelogenin and extracellular vesicles (EVs). Based on this concept, innovative surgeries, started in 2023 and which indeed appeared to rescue buccal development, will be followed-up. WorkPackage WP1 will analyze ERS anatomical profiles, cells and minerals in vivo and in vitro. This will provide a natural history of the disease from clinics to bench until the nanometer scale. In WP2, EVs will be purified from diseased and control cells, characterized and their functions, studied in vitro and in vivo by injecting EVs intravenously in control mice. The required EVs-specific skills are given by Partner 3. Together, the project will evidence the overall progression of ERS malformation and ectopic mineralization and rely it to the composition in proteins and nucleic acids (including miRNAs) and role of EVs. We expect to obtain different EVs profiles between healthy and ERS cells, as putative markers in body fluids or therapeutic agents in the future. Back from bench to clinics (WP3), all along WP1 and 2 during 4 years, ERS patient management will be designed and validated. In fine, the generated breakthroughs, bioressources and knowledge will pave the way of PHRC and international guidelines to implement in a consortium we will set up all along the project advancement.