Oro-Dental Manifestations in Loeys-Deitz Syndrome Mouse Models

Objectives: Objective: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder with mutations in TGF-Beta signaling pathway genes: TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3. The most common features reported include hypertelorism, abnormal uvula (broad or bifid) or cleft palate, craniosynostosis and widespread aortic and arterial aneurysm and tortuosity. However, the oro-dental manifestations are poorly characterized. Our aim is to study the changes in dento-alveolar tissues in LDS type 1 and 2 mouse models.
Methods: Methods: LDS types Type 1 and 2 mouse models have been generated previously, by targeting 2 missense mutations, to their respective endogenous locus in either the Tgfbr1 (M318R) or Tgfbr2 (G357W) gene. We characterized the mandibles of mice recapitulating LDS Type 1 and Type 2 mutations using X-ray radiography, histology, microCT and scanning electron microscopy. Two groups, 6-week (young) and 24-week (old) mice, within each type were studied and compared with their age and gender matched littermates.
Results: Results: There was a decrease in volume and density of dentin in Type 2 mutant mice compared to Type 1 and wild type. The enamel demonstrated an altered structure in the teeth of both types when visualized under scanning electron microscope. Strikingly, the volume of enamel was increased in the LDS type 2 mice. There was also a significant decrease in the alveolar bone surrounding the teeth in both Type 1 and Type 2 mutant mice that progressively worsens with age. Both mutant types demonstrated varying degrees of craniofacial deformities including craniosynostosis.
Conclusions: Conclusion: These data indicate for the first time that dento-alveolar structures of multiple embryonic origins are affected in Loeys-Deitz syndrome and show that the Type 2 mutation has a more severe phenotype than Type 1 mutation, which is analogous to what is found in our patients (unpublished).