Mutations in WNT10B Are Identified in Individuals with Oligodontia

Am J Hum Genet. 2016 Jul 7;99(1):195-201. doi: 10.1016/j.ajhg.2016.05.012.

Ping Yu ¹, Wenli Yang ², Dong Han ³, Xi Wang ², Sen Guo ¹, Jinchen Li ¹, Fang Li ³, Xiaoxia Zhang ³, Sing-Wai Wong ⁴, Baojing Bai ⁵, Yao Liu ⁶, Jie Du ⁷, Zhong Sheng Sun ⁸, Songtao Shi ⁶, Hailan Feng ⁹, Tao Cai ¹⁰

Affiliations

1 Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
2 Stomatological Hospital, Zhengzhou University, Zhengzhou 450052, China.
3 Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China.
4 Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China; Oral Biology Curriculum, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5 Department of Prosthodontics, Beijing Stomatology Hospital, Beijing 100050, China.
6 Department of Anatomy & Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
7 Beijing Anzhen Hospital, Capital Medical University, Beijing 100000, China.
8 Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100000, China.
9 Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China. Electronic address: kqfenghl@bjmu.edu.cn.
10 Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China; National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20982, USA. Electronic address: tcai@mail.nih.gov.

PMID: 27321946 DOI: 10.1016/j.ajhg.2016.05.012

Abstract

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.

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