FAM20C and FAM20A in normal and ectopic mineralization: A focus on oro-renal syndromes

FAM20C is part of the FAM20 family and is crucial for phosphorylating secreted proteins. It plays roles in various biological processes, including cellular calcium regulation and cardiovascular function. Pathogenic variants of FAM20C cause Raine syndrome, resulting in osteosclerotic dysplasia or hypophosphatemic rickets. Its paralog, FAM20A, is a secreted pseudokinase needed for optimal FAM20C activity. Mutations in FAM20A cause Enamel-Renal Syndrome. Common features in both syndromes include Amelogenesis Imperfecta, gingival fibromatosis and ectopic mineralization. We summarize current knowledge about the activity, interactions and regulation of FAM20C and FAM20A, with a focus on the possible role of bioactive lipids like sphingosine in activating FAM20C. We highlight the involvement of FAM20A and FAM20C in gingival fibromatosis, a fibrocalcifying disorder directly linked to the dysfunction of these proteins and the underlying molecular mechanisms. Additionally, we provide an overview of how FAM20C and FAM20A influence calcium homeostasis and mineralization. Since FAM20C-mediated phosphorylation is crucial in oral health, we detail how specific substrates such as osteopontin, periostin, or fetuin contribute to normal and ectopic mineralization and periodontal health. Although many questions about the roles of FAM20A and FAM20C in both oral and systemic diseases remain unresolved, targeting their activities could offer promising therapeutic options.