Luo Wendi, Yue Haitang, Song Guangtai, Cheng Jing, He Miao
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.
Mol Genet Genomic Med. 2025 May;13(5):e70101. doi: 10.1002/mgg3.70101.
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.
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.
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.
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.
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。
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。
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。
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。
