Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis

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, <...

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Autores principales:	Kuan-Yu Chu, Yin-Lin Wang, Yu-Ren Chou, Jung-Tsu Chen, Yi-Ping Wang, James P. Simmer, Jan C.-C. Hu, Shih-Kai Wang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	hypodontia oligodontia tooth development WNT signaling genetic mutation exome sequencing Medicine R
Acceso en línea:	https://doaj.org/article/7010d9472b9941fe97bb3be5e2920a47
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spelling	oai:doaj.org-article:7010d9472b9941fe97bb3be5e2920a472021-11-25T18:08:05ZSynergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis10.3390/jpm111112172075-4426https://doaj.org/article/7010d9472b9941fe97bb3be5e2920a472021-11-01T00:00:00Zhttps://www.mdpi.com/2075-4426/11/11/1217https://doaj.org/toc/2075-4426Familial 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 <i>AXIN2</i> <i>WNT10A</i>, <i>WNT10B</i>, <i>LRP6</i>, and <i>KREMEN1,</i> 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 <i>LRP6</i> 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 <i>LRP6</i> mutant allele and a <i>WNT10A</i> variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic <i>LRP6</i> mutations in a patient with many missing teeth further supported the dose-dependence of <i>LRP6</i>-associated FTA. Analysis of 21 FTA cases with 15 different <i>LRP6</i> 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.Kuan-Yu ChuYin-Lin WangYu-Ren ChouJung-Tsu ChenYi-Ping WangJames P. SimmerJan C.-C. HuShih-Kai WangMDPI AGarticlehypodontiaoligodontiatooth developmentWNT signalinggenetic mutationexome sequencingMedicineRENJournal of Personalized Medicine, Vol 11, Iss 1217, p 1217 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hypodontia oligodontia tooth development WNT signaling genetic mutation exome sequencing Medicine R
spellingShingle	hypodontia oligodontia tooth development WNT signaling genetic mutation exome sequencing Medicine R Kuan-Yu Chu Yin-Lin Wang Yu-Ren Chou Jung-Tsu Chen Yi-Ping Wang James P. Simmer Jan C.-C. Hu Shih-Kai Wang Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis
description	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 <i>AXIN2</i> <i>WNT10A</i>, <i>WNT10B</i>, <i>LRP6</i>, and <i>KREMEN1,</i> 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 <i>LRP6</i> 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 <i>LRP6</i> mutant allele and a <i>WNT10A</i> variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic <i>LRP6</i> mutations in a patient with many missing teeth further supported the dose-dependence of <i>LRP6</i>-associated FTA. Analysis of 21 FTA cases with 15 different <i>LRP6</i> 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.
format	article
author	Kuan-Yu Chu Yin-Lin Wang Yu-Ren Chou Jung-Tsu Chen Yi-Ping Wang James P. Simmer Jan C.-C. Hu Shih-Kai Wang
author_facet	Kuan-Yu Chu Yin-Lin Wang Yu-Ren Chou Jung-Tsu Chen Yi-Ping Wang James P. Simmer Jan C.-C. Hu Shih-Kai Wang
author_sort	Kuan-Yu Chu
title	Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis
title_short	Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis
title_full	Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis
title_fullStr	Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis
title_full_unstemmed	Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis
title_sort	synergistic mutations of <i>lrp6</i> and <i>wnt10a</i> in familial tooth agenesis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7010d9472b9941fe97bb3be5e2920a47
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_version_	1718411564484132864

Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> in Familial Tooth Agenesis

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