Duverger O, Wang S K, Liu Q N, Wang Y, Martin D, Baena V, Syed Z A, Mendoza F, Nguyen T T, Frischmeyer-Guerrerio P A, Jani P H, Lee J S
Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Mass Spectrometry Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
J Dent Res. 2025 Jul;104(8):840-850. doi: 10.1177/00220345251326094. Epub 2025 Apr 22.
Loeys-Dietz syndrome (LDS1-6) is caused by mutations along the transforming growth factor-β (TGF-β) signaling pathway and features aortic aneurysms and craniofacial dysmorphology. Mutations that cause LDS can be found in the genes encoding transforming growth factor-β (TGF-β) ligands ( and ), receptors ( and ), and signal transducers ( and ). Variable enamel anomalies are seen in patients with LDS, but the most severe enamel defects with advanced attrition have been observed specifically in some patients with mutation in the gene (LDS2). We used human specimens as well as a mouse model to further characterize enamel defects in LDS2 and to investigate the mechanism that leads to this phenotype. Deciduous teeth from patients with LDS2 exhibited normal enamel thickness, normal or localized reduction in enamel mineral density, impaired enamel ultrastructure, and impaired biomechanical properties, with some changes likely associated with environmental and systemic effects. Mice with mutation in the gene exhibited no significant changes in the amount of enamel produced or degree of mineralization. However, they presented with unique disruption of enamel rod decussation (crisscross pattern), resulting in impaired biomechanical properties. This phenotype is caused by impaired coordinated movement of ameloblasts (enamel-producing cells) during matrix deposition. Molecular analyses revealed that mutation in in ameloblasts does not significantly affect pSMAD2/3 levels in vivo and has a minimal effect on gene expression in the enamel organ when compared with the aorta, in which hundreds of genes were differentially expressed and consistent with aortic aneurysm. However, we identified changes in the distribution and activation of the metastasis suppressor NDRG1, Rac1/Cdc42, and Myosin II that appear consistent with the disruption of ameloblast coordinated movement, although the exact mechanism through which mutation in causes this unique enamel phenotype remains to be elucidated.
洛伊氏综合征（LDS1 - 6）由转化生长因子-β（TGF-β）信号通路中的突变引起，其特征为主动脉瘤和颅面畸形。导致LDS的突变可在编码转化生长因子-β（TGF-β）配体（ 和 ）、受体（ 和 ）以及信号转导分子（ 和 ）的基因中发现。LDS患者可见多种牙釉质异常，但在某些 基因突变（LDS2）的患者中特别观察到了伴有严重磨耗的最严重牙釉质缺陷。我们使用人体标本以及小鼠模型进一步表征LDS2中的牙釉质缺陷，并研究导致这种表型的机制。LDS2患者的乳牙显示出牙釉质厚度正常、牙釉质矿物质密度正常或局部降低、牙釉质超微结构受损以及生物力学性能受损，其中一些变化可能与环境和全身影响有关。 基因突变的小鼠在牙釉质生成量或矿化程度上没有显著变化。然而，它们出现了独特的釉柱交叉（十字交叉模式）破坏，导致生物力学性能受损。这种表型是由成釉细胞（产生牙釉质的细胞）在基质沉积过程中协调运动受损引起的。分子分析表明，与主动脉相比，成釉细胞中的 突变在体内不会显著影响pSMAD2/3水平，对牙釉质器官中的基因表达影响极小，在主动脉中数百个基因差异表达且与主动脉瘤一致。然而，我们发现转移抑制因子NDRG1、Rac1/Cdc42和肌球蛋白II的分布和激活发生了变化，这些变化似乎与成釉细胞协调运动的破坏一致，尽管 突变导致这种独特牙釉质表型的确切机制仍有待阐明。
