Synergistic Mutations of <i>LRP6</i> and <i>WNT10A</i> 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 <i>AXIN2</i> <i>WNT10A</i>, <i>WNT10B</i>, <...
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| Autores principales: | , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/7010d9472b9941fe97bb3be5e2920a47 |
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| Sumario: | 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. |
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