Genetic Variants in KIF7 May Contribute to Supernumerary Tooth Formation

Abstract

Objective: Kinesin Family Member 7 (KIF7) regulates ciliary integrity. Cilia-mediated sonic hedgehog signalling regulates tooth number, position, and morphology. The objective of the study was to investigate whether KIF7 variants could contribute to the formation of supernumerary teeth.

Methods: Whole-exome sequencing was performed on 153 individuals from 130 families with isolated supernumerary tooth types. Immunohistochemistry of Kif7 expression during early odontogenesis was performed in mouse embryos. Mutant KIF7 protein models were generated.

Results: We identified 4 rare missense variants (c.160C>T;p.His54Tyr, c.175G>A;p.Val59Met, c.1964C>G;p.Pro655Arg, and c.2551C>T;p.Arg851Cys), 1 novel missense variant (c.1882 G>A;p.Glu628Lys), and 1 insertion variant (c.1893_1894insGAGGAG;p.Glu630_Glu631dup) in the KIF7 gene in patients with various orodental presentations: 5 individuals from 4 families with mesiodens, 1 proband with a supernumerary molar, and 1 proband with a compound odontoma. The p.His54Tyr and p.Val59Met variants, located in the motor domain of the KIF7 protein, are predicted to disrupt its interaction with tubulin, resulting in abnormal localisation of KIF7 in cilia. The Arg851Cys variant in the coiled-coil region and the Glu628Lys, Glu630_Glu631dup, and Pro655Arg variants in the region of unknown structure are predicted to disrupt charge balance.

Conclusion: This is the first report demonstrating that KIF7 variants may be contributing factors to supernumerary tooth phenotypes.

Keywords: Ciliopathy; Mesiodens; Odontoma; SHH signalling; Supernumerary teeth; WNT signalling.