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与非综合征性牙齿发育不全相关的AXIN2和LRP6新突变的鉴定及功能分析

Identification and Functional Analysis of Novel Mutations in AXIN2 and LRP6 Linked With Non-Syndromic Tooth Agenesis.

作者信息

Luo Wendi, Yue Haitang, Song Guangtai, Cheng Jing, He Miao

机构信息

State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.

Department of Paediatric Dentistry, School and Hospital of Stomatology, Wuhan University, Wuhan, China.

出版信息

Mol Genet Genomic Med. 2025 May;13(5):e70101. doi: 10.1002/mgg3.70101.

DOI:10.1002/mgg3.70101
PMID:40293036
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12035762/
Abstract

BACKGROUND: Tooth agenesis (TA) ranks among the most common dental abnormalities. This study aimed to explore the etiology and pathogenesis in Chinese families with non-syndromic TA. METHODS: Chinese families exhibiting non-syndromic TA were recruited. Exome sequencing was conducted to identify mutations in the candidate genes, followed by Sanger sequencing for validation. Functional studies, including bioinformatics analyses, western blots, and dual-luciferase assays, were performed to analyze the impact of the two mutations on the Wnt/β-catenin pathway. RESULTS: We identified a novel heterozygous frameshift insertion in AXIN2 [NM_001363813.1: c.1799dupG (p.Asn601GlnfsTer41)] and a novel de novo heterozygous non-frameshift deletion in LRP6 [NM_002336.3: c.3074_3082del (p.1025_1028del)]. Further functional studies indicated that AXIN2 p.Asn601GlnfsTer41 caused hyperactivation of the Wnt/β-catenin pathway, and LRP6 p.1025_1028del led to pathway suppression. CONCLUSIONS: This study expands the spectrum of AXIN2 and LRP6 mutations associated with non-syndromic TA. Our study provided further functional evidence supporting the pathogenicity of suppression and excessive activation of the Wnt signaling pathway in TA.

摘要

背景：牙齿发育不全（TA）是最常见的牙齿异常之一。本研究旨在探讨中国非综合征性TA家系的病因及发病机制。 方法：招募表现为非综合征性TA的中国家系。进行外显子组测序以鉴定候选基因中的突变，随后进行Sanger测序验证。进行功能研究，包括生物信息学分析、蛋白质免疫印迹和双荧光素酶测定，以分析这两种突变对Wnt/β-连环蛋白信号通路的影响。 结果：我们在AXIN2基因中鉴定出一个新的杂合移码插入突变[NM_001363813.1: c.1799dupG (p.Asn601GlnfsTer41)]，以及在LRP6基因中鉴定出一个新的新生杂合非移码缺失突变[NM_002336.3: c.3074_3082del (p.1025_1028del)]。进一步的功能研究表明，AXIN2 p.Asn601GlnfsTer41导致Wnt/β-连环蛋白信号通路过度激活，而LRP6 p.1025_1028del导致该信号通路受抑制。 结论：本研究扩展了与非综合征性TA相关的AXIN2和LRP6基因突变谱。我们的研究提供了进一步的功能证据，支持Wnt信号通路抑制和过度激活在TA发病机制中的致病性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/c2e7f40559dc/MGG3-13-e70101-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/256e6b11fbbe/MGG3-13-e70101-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/0f8777506f1a/MGG3-13-e70101-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/b2723ef59d50/MGG3-13-e70101-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/6e86b39bb716/MGG3-13-e70101-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/c2e7f40559dc/MGG3-13-e70101-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/256e6b11fbbe/MGG3-13-e70101-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/0f8777506f1a/MGG3-13-e70101-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/b2723ef59d50/MGG3-13-e70101-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/6e86b39bb716/MGG3-13-e70101-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6c7/12035762/c2e7f40559dc/MGG3-13-e70101-g001.jpg

相似文献

[1]
Identification and Functional Analysis of Novel Mutations in AXIN2 and LRP6 Linked With Non-Syndromic Tooth Agenesis.

Mol Genet Genomic Med. 2025-5

[2]
Functional analysis of a novel missense mutation in AXIN2 associated with non-syndromic tooth agenesis.

Eur J Oral Sci. 2016-6

[3]
Genetic analysis: Wnt and other pathways in nonsyndromic tooth agenesis.

Oral Dis. 2018-7-23

[4]
Loss-of-Function Mutations in the WNT Co-receptor LRP6 Cause Autosomal-Dominant Oligodontia.

Am J Hum Genet. 2015-10-1

[5]
A novel missense mutation of LRP6 identified by whole-exome sequencing in a Chinese family with non-syndromic tooth agenesis.

Orthod Craniofac Res. 2021-5

[6]
Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

Genet Med. 2016-11

[7]
Dynamic Expression in Tooth Development and Mutations in Oligodontia.

J Dent Res. 2021-4

[8]
Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

J Dent Res. 2018-1

[9]
Genetic study of non-syndromic tooth agenesis through the screening of paired box 9, msh homeobox 1, axin 2, and Wnt family member 10A genes: a case-series.

Eur J Oral Sci. 2018-2

[10]
Identification of a novel missense heterozygous mutation in the KDF1 gene for non-syndromic congenital anodontia.

Clin Oral Investig. 2022-8

引用本文的文献

[1]
Genetic Aspects of Tooth Agenesis.

Genes (Basel). 2025-5-15

本文引用的文献

[1]
Mutations in LRP6 highlight the role of WNT signaling in oral exostoses and dental anomalies.

Arch Oral Biol. 2022-10

[2]
Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities.

Signal Transduct Target Ther. 2022-1-3

[3]
LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence.

Front Cell Dev Biol. 2021-5-6

[4]
Dynamic Expression in Tooth Development and Mutations in Oligodontia.

J Dent Res. 2021-4

[5]
A novel missense mutation of LRP6 identified by whole-exome sequencing in a Chinese family with non-syndromic tooth agenesis.

Orthod Craniofac Res. 2021-5

[6]
Genetic analysis: Wnt and other pathways in nonsyndromic tooth agenesis.

Oral Dis. 2018-7-23

[7]
Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese.

Genome Med. 2017-11-17

[8]
Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

J Dent Res. 2018-1

[9]
Patterns of non-syndromic permanent tooth agenesis in a large orthodontic population.

Arch Oral Biol. 2017-7

[10]
Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

Genet Med. 2016-11

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