SLC4A9 deficiency is involved in Sjögren’s syndrome and enamel defects through RPS27-triggered ribosomal stress

Abstract Xerostomia, a salivary gland disorder affecting up to 30% of adults, compromises oral homeostasis by reducing salivary flow and buffering capacity. Amelogenesis imperfecta is a hereditary condition characterized by defective enamel formation and mineralization, with a prevalence ranging from 1 in 700 to 1 in 14,000 children worldwide. Although xerostomia has been associated with increased susceptibility to dental caries and subsequent enamel damage, its relationship with amelogenesis imperfecta remains unclear, and no shared molecular pathway has been causally linked to both hyposalivation and enamel malformation. Notably, several Cl − /HCO 3 − exchangers regulate ion transport and pH homeostasis, thereby influencing salivary secretion as well as enamel maturation and mineralization, raising the possibility that these transporters may serve as a common molecular link between xerostomia and amelogenesis imperfecta. Here, we report the identification of SLC4A9, a Na + -dependent Cl − /HCO 3 − exchanger whose dysfunction simultaneously disrupts salivary secretion and enamel mineralization. Genetic analyses identified variations in the SLC4A9 gene, including missense mutations in three cases of amelogenesis imperfecta and copy number variations with reduced SLC4A9 expression in a patient with Sjögren’s syndrome. Slc4a9 knockout mice exhibited dual pathological phenotypes, including salivary impairment with reduced secretion, female-predominant glandular inflammation and autoantibody production, as well as enamel malformation with delayed ameloblast differentiation. Mechanistically, SLC4A9 deficiency disrupted Cl − /pH homeostasis, leading to RPS27 upregulation and ribosomal stress, which in turn activated p53-dependent cell-cycle arrest and apoptosis in both glandular and enamel lineages. Treatment with the MDM2 antagonist Nutlin-3a reduced salivary inflammation, supporting the therapeutic potential of this pathway. Collectively, these findings suggest that xerostomia and amelogenesis imperfecta represent overlapping phenotypes driven by variations in the same gene and a shared mechanism of ribosomal stress-associated apoptosis, despite occurring in distinct tissues. This work highlights a unified diagnostic target and potential therapeutic strategy for restoring both salivary function and enamel integrity.