Rare Genetic Variants in Human APC Are Implicated in Mesiodens and Isolated Supernumerary Teeth.

The activation of Wnt/ß-catenin signalling is a prerequisite for odontogenesis. APC, a member of the AXIN-CK1-GSK3ß-APC ß-catenin destruction complex, functions to modulate Wnt/ß-catenin signalling to establish regular teeth number and positions. APC loss-of-function mutations are associated with the over-activation of WNT/ß-catenin signalling and subsequent familial adenomatous polyposis (FAP; MIM 175100) with or without multiple supernumerary teeth. The ablation of Apc function in mice also results in the constitutive activation of ß-catenin in embryonic mouse epithelium and causes supernumerary tooth formation. The objective of this study was to investigate if genetic variants in the APC gene were associated with supernumerary tooth phenotypes. We clinically, radiographically, and molecularly investigated 120 Thai patients with mesiodentes or isolated supernumerary teeth. Whole exome and Sanger sequencing identified three extremely rare heterozygous variants (c.3374T>C, p.Val1125Ala; c.6127A>G, p.Ile2043Val; and c.8383G>A, p.Ala2795Thr) in APC in four patients with mesiodentes or a supernumerary premolar. An additional patient with mesiodens was compound as heterozygous for two APC variants (c.2740T>G, p.Cys914Gly, and c.5722A>T, p.Asn1908Tyr). Rare variants in APC in our patients are likely to contribute to isolated supernumerary dental phenotypes including isolated mesiodens and an isolated supernumerary tooth.

A Mutation in CACNA1S Is Associated with Multiple Supernumerary Cusps and Root Maldevelopment.

BACKGROUND: Enamel knots and Hertwig epithelial root sheath (HERS) regulate the growth and folding of the dental epithelium, which subsequently determines the final form of tooth crown and roots. We would like to investigate the genetic etiology of seven patients affected with unique clinical manifestations, including multiple supernumerary cusps, single prominent premolars, and single-rooted molars. METHODS: Oral and radiographic examination and whole-exome or Sanger sequencing were performed in seven patients. Immunohistochemical study during early tooth development in mice was performed. RESULTS: A heterozygous variant (c. 865A>G; p.Ile289Val) in CACNA1S was identified in all the patients, but not in an unaffected family member and control. Immunohistochemical study showed high expression of Cacna1s in the secondary enamel knot. CONCLUSIONS: This CACNA1S variant seemed to cause impaired dental epithelial folding; too much folding in the molars and less folding in the premolars; and delayed folding (invagination) of HERS, which resulted in single-rooted molars or taurodontism. Our observation suggests that the mutation in CACNA1S might disrupt calcium influx, resulting in impaired dental epithelium folding, and subsequent abnormal crown and root morphology.