Distinctive Amelogenesis Imperfecta in Loeys–Dietz Syndrome Type II

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 (<i>TGFB2</i> and <i>TGFB3</i>), receptors (<i>TGFBR1</i> and <i>TGFBR2</i>), and signal transducers (<i>SMAD2</i> and <i>SMAD3</i>). 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 <i>TGFBR2</i> 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 <i>Tgfbr2</i> 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 <i>Tgfbr2</i> 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 <i>Tgfbr2</i> causes this unique enamel phenotype remains to be elucidated.