Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China.
Division of Comprehensive Oral Care-Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J Dent Res. 2021 Apr;100(4):415-422. doi: 10.1177/0022034520970459. Epub 2020 Nov 9.
Genes associated with the WNT pathway play an important role in the etiology of tooth agenesis. Low-density lipoprotein receptor-related protein 6 encoding gene () is a recently defined gene that is associated with autosomal dominant inherited tooth agenesis. Here, we aimed to identify novel mutations in patients with tooth agenesis and investigate the significance of during tooth development. Using whole-exome sequencing, we identified 4 novel heterozygous mutations (c.2292G>A, c.195dup, c.1095dup, and c.1681C>T) in 4 of 77 oligodontia patients. Notably, a patient who carried a nonsense mutation (c.2292G>A; p.W764*) presented a hypohidrotic ectodermal dysplasia phenotype. Preliminary functional studies, including bioinformatics analysis and TOP-/FOP-flash reporter assays, demonstrated that the activation of WNT/β-catenin signaling was compromised as a consequence of mutations. RNAscope in situ hybridization revealed dynamic and special changes of expression during murine tooth development from E11.5 to E16.5. It was noteworthy that was specifically expressed in the epithelium at E11.5 to E13.5 but was expressed in both dental epithelium and dental papilla from E14.5 and persisted in both tissues at later stages. Our study broadens the mutation spectrum of human tooth agenesis and is the first to identify a mutation in patients with hypohidrotic ectodermal dysplasia and reveal the dynamic expression pattern of during tooth development. Information from this study is conducive to understanding the functional significance of on the biological process of tooth development.
与 WNT 通路相关的基因在牙齿缺失的病因学中起着重要作用。低密度脂蛋白受体相关蛋白 6 编码基因 () 是最近定义的与常染色体显性遗传性牙齿缺失相关的基因。在这里，我们旨在鉴定牙齿缺失患者中的新突变，并研究在牙齿发育过程中的意义。使用全外显子组测序，我们在 77 名少牙症患者中的 4 名中发现了 4 个新的杂合突变 (c.2292G>A、c.195dup、c.1095dup 和 c.1681C>T)。值得注意的是，携带无义突变 (c.2292G>A;p.W764*)的患者表现出少汗性外胚层发育不良表型。初步功能研究，包括生物信息学分析和 TOP-/FOP-flash 报告基因检测，表明 WNT/β-catenin 信号通路的激活受到影响。RNAscope 原位杂交显示，在 E11.5 至 E16.5 的小鼠牙齿发育过程中， 表达出现动态和特殊变化。值得注意的是，在 E11.5 至 E13.5 时， 仅在牙上皮中特异性表达，但从 E14.5 开始在牙上皮和牙乳头中均有表达，并在后期的两个组织中持续表达。我们的研究拓宽了人类牙齿缺失的突变谱，首次在少汗性外胚层发育不良患者中发现了 突变，并揭示了 在牙齿发育过程中的动态表达模式。该研究提供的信息有助于理解在牙齿发育的生物学过程中 的功能意义。
