Abstract
Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/β-catenin signaling, including AXIN2 WNT10A, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(Met168Arg), p.(Ala754Pro), and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an LRP6 mutant allele and a WNT10A variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic LRP6 mutations in a patient with many missing teeth further supported the dose-dependence of LRP6-associated FTA. Analysis of 21 FTA cases with 15 different LRP6 loss-of-function mutations revealed high heterogeneity of disease severity and a distinctive pattern of missing teeth, with maxillary canines being frequently affected. We hypothesized that various combinations of sequence variants in WNT-related genes can modulate WNT signaling activities during tooth development and cause a wide spectrum of tooth agenesis severity, which highlights the importance of exome/genome analysis for the genetic diagnosis of FTA in this era of precision medicine.
Highlights
Introduction with regard to jurisdictional claims inTooth formation is a developmental process hinged on epithelial–mesenchymal interactions that require intricate regulation of many transcription factors, morphogenic molecules, and signaling pathways [1]
Academic Editor: Department of Dentistry, School of Dentistry, National Taiwan University, Taipei City 100, Taiwan; Department of Pediatric Dentistry, National Taiwan University Children’s Hospital, Taipei City 100, Taiwan
The panoramic radiograph revealed a total of eight missing permanent teeth excluding third molars (Figures 1C and S1C) (Table 1)
Summary
Tooth formation is a developmental process hinged on epithelial–mesenchymal interactions that require intricate regulation of many transcription factors, morphogenic molecules, and signaling pathways [1]. Non-syndromic FTA [4], including MSX1 (OMIM*142983) [5], PAX9 (OMIM*167416) [6], AXIN2 (OMIM*604025) [7], EDA (OMIM*300451) [8], WNT10A (OMIM*606268) [9], and LRP6 (OMIM*603507) [10,11] As these genes function in organogenesis other than tooth formation, their mutations can cause non-dental phenotypes in affected individuals, such as hair, nail, or sweating problems, except for PAX9 [4]. LRP6 (Low Density Lipoprotein Receptor-related Protein 6) is a gene that encodes a cell surface receptor belonging to the low density lipoprotein receptor (LDLR) family [14] It serves as a co-receptor for WNT/β-catenin signaling, along with its Drosophila homolog. Two probands with severe oligodontia carried LRP6 mutations and WNT10A pathogenic variants, suggesting a potential mutational synergism or digenic inheritance for WNT signaling-related genes in FTA. We further delineated a specific pattern of tooth agenesis caused by LRP6 loss-of-function mutations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
