The Enamel Phenotype in Homozygous Fam83h Truncation Mice.

BACKGROUND: Truncation FAM83H mutations cause human autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), an inherited disorder characterized by severe hardness defects in dental enamel. No enamel defects were observed in Fam83h null mice suggesting that Fam83h truncation mice would better replicate human mutations. METHODS: We generated and characterized a mouse model (Fam83h(Tr/Tr) ) expressing a truncated FAM83H protein (amino acids 1-296), which recapitulated the ADHCAI-causing human FAM83H p.Tyr297* mutation. RESULTS: Day 14 and 7-week Fam83h(Tr/Tr) molars exhibited rough enamel surfaces and slender cusps resulting from hypoplastic enamel defects. The lateral third of the Fam83h(Tr/Tr) incisor enamel layer was thinner, with surface roughness and altered enamel rod orientation, suggesting disturbed enamel matrix secretion. Regular electron density in mandibular incisor enamel indicated normal enamel maturation. Only mildly increased posteruption attrition of Fam83h(Tr/Tr) molar enamel was observed at 7-weeks. Histologically, the Fam83h(Tr/Tr) enamel organ, including ameloblasts, and enamel matrices at sequential stages of amelogenesis exhibited comparable morphology without overt abnormalities, except irregular and less evident ameloblast Tomes' processes in specific areas. CONCLUSIONS: Considering Fam83h(-/-) mice showed no enamel phenotype, while Fam83h(Tr/Tr) (p.Tyr297*) mice displayed obvious enamel malformations, we conclude that FAM83H truncation mutations causing ADHCAI in humans disturb amelogenesis through a neomorphic mechanism, rather than haploinsufficiency.