Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis
| Autor: | Xu Chen, Kai Yang, Chun-yan Zheng, Xing-yue Dong, Yan-xia Huang, Chun-yan Gao, Yong-qing Sun, You-sheng Yan, Dong‐liang Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Proband In silico Biology QH426-470 medicine.disease_cause experimental study LRP6 gene 03 medical and health sciences 0302 clinical medicine medicine Genetics Missense mutation whole-exome sequencing Gene Genetics (clinical) Exome sequencing Original Research molecular dynamics analysis Mutation Wnt signaling pathway LRP6 030206 dentistry 030104 developmental biology Molecular Medicine tooth agenesis |
| Zdroj: | Frontiers in Genetics, Vol 12 (2021) Frontiers in Genetics |
| ISSN: | 1664-8021 |
| DOI: | 10.3389/fgene.2021.688241/full |
| Popis: | BackgroundThe low-density lipoprotein receptor-related protein 6 (LRP6) gene is a recently defined gene that is associated with the autosomal-dominant inherited tooth agenesis (TA). In the present study, a family of four generations having TA was recruited and subjected to a series of clinical, genetic, in silico, and in vitro investigations.MethodsAfter routine clinical evaluation, the proband was subjected to whole-exome sequencing (WES) to detect the diagnostic variant. Next, in silico structural and molecular dynamics (MD) analysis was conducted on the identified novel missense variant for predicting its intramolecular impact. Subsequently, an in vitro study was performed to further explore the effect of this variant on protein maturation and phosphorylation.ResultsWES identified a novel variant, designated as LRP6: c.2570G > A (p.R857H), harbored by six members of the concerned family, four of whom exhibited varied TA symptoms. The in silico analysis suggested that this novel variant could probably damage the Wnt bonding function of the LRP6 protein. The experimental study demonstrated that although this novel variant did not affect the LRP6 gene transcription, it caused a impairment in the maturation and phosphorylation of LRP6 protein, suggesting the possibility of the disruption of the Wnt signaling.ConclusionThe present study expanded the mutation spectrum of human TA in the LRP6 gene. The findings of the present study are insightful and conducive to understanding the functional significance of specific LRP6 variants. |
| Databáze: | OpenAIRE |
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