The Enamel Phenotype in Homozygous Fam83h Truncation Mice

BackgroundTruncation 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.MethodsWe generated and characterized a mouse model (Fam83hTr/Tr) expressing a truncated FAM83H protein (amino acids 1â 296), which recapitulated the ADHCAIâ causing human FAM83H p.Tyr297* mutation.ResultsDay 14 and 7â week Fam83hTr/Tr molars exhibited rough enamel surfaces and slender cusps resulting from hypoplastic enamel defects. The lateral third of the Fam83hTr/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 Fam83hTr/Tr molar enamel was observed at 7â weeks. Histologically, the Fam83hTr/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.ConclusionsConsidering Fam83hâ /â mice showed no enamel phenotype, while Fam83hTr/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.FAM83H truncation mutations cause inherited enamel malformations in humans. Previously we showed that no enamel malformations are observed in Fam83h null mice. Here we demonstrate that truncation of FAM83H in mice causes enamel malformations. This figure shows how the lateral incisor enamel (on the left) is thinner in the Fam83h truncation mouse than it is in wild-type.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149571/1/mgg3724-sup-0004-DataS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149571/2/mgg3724-sup-0003-DataS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149571/3/mgg3724-sup-0001-DataS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149571/4/mgg3724-sup-0002-DataS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149571/5/mgg3724_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149571/6/mgg3724.pd