Delayed Tooth Eruption Caused By Fam83h Truncating Mutation

Approximately 25% of patients with autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), caused by FAM83H truncating mutations, exhibit abnormal tooth eruption, which disrupts maxillofacial development and function. However, the underlying mechanisms by which FAM83H mutations contribute to this phenotype remain unclear. Fam83h c.1186C > T (p.Q396*) knock-in mice were generated using CRSIPR-Cas9 technology. Tooth eruption was evaluated using micro-CT and histological analysis. Osteoclastic activity in the alveolar bone surrounding the tooth bud was assessed via tartrate-resistant acid phosphatase (TRAP) staining. Additionally, tissues involved in the tooth eruption process, including the dental follicle and enamel organ, were analyzed for osteoclast-regulating cytokines using qPCR, western blotting, and immunohistochemistry. The erupting teeth of homozygous mutant mice showed a delay in penetrating the alveolar bone surface and a significantly reduced eruption rate compared to wild-type and heterozygous littermates. TRAP staining revealed a marked reduction in osteoclastic activity within the alveolar bone surrounding the erupting tooth. Notably, the enamel organ, rather than the dental follicle, of homozygous mice exhibited significantly decreased expression of parathyroid hormone-related protein (PTHrP) and macrophage colony-stimulating factor (M-CSF), both of which are key regulators of osteoclastic activity during intraosseous tooth eruption. These findings indicate that Fam83h truncating mutations impair tooth eruption by reducing osteoclastic activity in the surrounding alveolar bone. The diminished expression of PTHrP and M-CSF in the enamel organ plays a critical regulatory role in this process.