Mutations in WNT10B Are Identified in Individuals with Oligodontia

Supplemental Data Supplemental Data include six figures and three tables and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2016.05.012. Supplemental Data Document S1. Figures S1–S6 and Tables S1–S3 Download Document S2. Article plus Supplemental Data Download Web Resources Allen Brain Atlas, http://www.brain-map.org/ Eurexpress, http://www.eurexpress.org/ee/ ExAC Browser, http://exac.broadinstitute.org/ GEO Profiles, http://www.ncbi.nlm.nih.gov/geoprofiles HGMD, http://www.biobase-international.com/product/hgmd MutationTaster, http://www.mutationtaster.org/ OMIM, http://www.omim.org RefSeq, http://www.ncbi.nlm.nih.gov/refseq/ Tooth agenesis is one of the most common developmental anomalies in humans. Oligodontia, a severe form of tooth agenesis, is genetically and phenotypically a heterogeneous condition. Although significant efforts have been made, the genetic etiology of dental agenesis remains largely unknown. In the present study, we performed whole-exome sequencing to identify the causative mutations in Chinese families in whom oligodontia segregates with dominant inheritance. We detected a heterozygous missense mutation (c.632G>A [p.Arg211Gln]) in WNT10B in all affected family members. By Sanger sequencing a cohort of 145 unrelated individuals with non-syndromic oligodontia, we identified three additional mutations (c.569C>G [p.Pro190Arg], c.786G>A [p.Trp262∗], and c.851T>G [p.Phe284Cys]). Interestingly, analysis of genotype-phenotype correlations revealed that mutations in WNT10B affect the development of permanent dentition, particularly the lateral incisors. Furthermore, a functional assay demonstrated that each of these mutants could not normally enhance the canonical Wnt signaling in HEPG2 epithelial cells, in which activity of the TOPFlash luciferase reporter was measured. Notably, these mutant WNT10B ligands could not efficiently induce endothelial differentiation of dental pulp stem cells. Our findings provide the identification of autosomal-dominant WNT10B mutations in individuals with oligodontia, which increases the spectrum of congenital tooth agenesis and suggests attenuated Wnt signaling in endothelial differentiation of dental pulp stem cells