Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis
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, gene...
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doaj-6706a3004e4045cf9e2f5fe58f6a28e32021-07-07T05:44:12ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-07-011210.3389/fgene.2021.688241688241Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth AgenesisYan-xia Huang0Chun-yan Gao1Chun-yan Zheng2Xu Chen3You-sheng Yan4Yong-qing Sun5Xing-yue Dong6Kai Yang7Dong-liang Zhang8Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, ChinaDepartment of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, ChinaDepartment of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, ChinaDepartment of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, ChinaPrenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, ChinaPrenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, ChinaDepartment of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, ChinaPrenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, ChinaDepartment of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, ChinaBackgroundThe 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.https://www.frontiersin.org/articles/10.3389/fgene.2021.688241/fulltooth agenesisLRP6 genewhole-exome sequencingmolecular dynamics analysisexperimental study |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yan-xia Huang Chun-yan Gao Chun-yan Zheng Xu Chen You-sheng Yan Yong-qing Sun Xing-yue Dong Kai Yang Dong-liang Zhang |
spellingShingle |
Yan-xia Huang Chun-yan Gao Chun-yan Zheng Xu Chen You-sheng Yan Yong-qing Sun Xing-yue Dong Kai Yang Dong-liang Zhang Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis Frontiers in Genetics tooth agenesis LRP6 gene whole-exome sequencing molecular dynamics analysis experimental study |
author_facet |
Yan-xia Huang Chun-yan Gao Chun-yan Zheng Xu Chen You-sheng Yan Yong-qing Sun Xing-yue Dong Kai Yang Dong-liang Zhang |
author_sort |
Yan-xia Huang |
title |
Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis |
title_short |
Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis |
title_full |
Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis |
title_fullStr |
Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis |
title_full_unstemmed |
Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis |
title_sort |
investigation of a novel lrp6 variant causing autosomal-dominant tooth agenesis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2021-07-01 |
description |
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. |
topic |
tooth agenesis LRP6 gene whole-exome sequencing molecular dynamics analysis experimental study |
url |
https://www.frontiersin.org/articles/10.3389/fgene.2021.688241/full |
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