Abstract
Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with amelogenesis imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation. Each of these homozygous variants (a large in-frame deletion, a frameshift deletion, and a missense variant) were predicted to result in loss of function. GPR68 encodes a proton-sensing G-protein-coupled receptor with sensitivity in the pH range that occurs in the developing enamel matrix during amelogenesis. Immunohistochemistry of rat mandibles confirmed localization of GPR68 in the enamel organ at all stages of amelogenesis. Our data identify a role for GPR68 as a proton sensor that is required for proper enamel formation.
Highlights
Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body
Mature enamel consists of highly organized calcium hydroxyapatite (Ca10[PO4]6[OH]2) crystals, which form in a discrete extracellular compartment within the developing tooth.[1]
Secretory-stage enamel contains a large volume of matrix proteins that might provide buffering capacity, during the maturation stage these proteins are degraded, and the rate of mineralization is at its highest
Summary
Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. Mature enamel consists of highly organized calcium hydroxyapatite (Ca10[PO4]6[OH]2) crystals, which form in a discrete extracellular compartment within the developing tooth.[1] Ameloblasts, the enamel-forming cells, regulate the mineralization of enamel by secreting matrix proteins that act as modulators of crystal deposition and growth.
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