RESUMO
CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.
Assuntos
Cateninas/genética , Fenda Labial/genética , Fissura Palatina/genética , Anormalidades Craniofaciais/genética , Ectrópio/genética , Cardiopatias Congênitas/genética , Anormalidades Dentárias/genética , Adolescente , Adulto , Animais , Anodontia/diagnóstico por imagem , Anodontia/genética , Anodontia/fisiopatologia , Criança , Pré-Escolar , Fenda Labial/diagnóstico por imagem , Fenda Labial/fisiopatologia , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/fisiopatologia , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/fisiopatologia , Modelos Animais de Doenças , Ectrópio/diagnóstico por imagem , Ectrópio/fisiopatologia , Feminino , Predisposição Genética para Doença , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Humanos , Masculino , Camundongos , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/fisiopatologia , Xenopus , Adulto Jovem , delta CateninaRESUMO
Canonical Wnt signaling coordinates many critical aspects of embryonic development, while dysregulated Wnt signaling contributes to common diseases, including congenital malformations and cancer. The nuclear localization of ß-catenin is the defining step in pathway activation. However, despite intensive investigation, the mechanisms regulating ß-catenin nuclear transport remain undefined. In a patient with congenital heart disease and heterotaxy, a disorder of left-right patterning, we previously identified the guanine nucleotide exchange factor, RAPGEF5. Here, we demonstrate that RAPGEF5 regulates left-right patterning via Wnt signaling. In particular, RAPGEF5 regulates the nuclear translocation of ß-catenin independently of both ß-catenin cytoplasmic stabilization and the importin ß1/Ran-mediated transport system. We propose a model whereby RAPGEF5 activates the nuclear GTPases, Rap1a/b, to facilitate the nuclear transport of ß-catenin, defining a parallel nuclear transport pathway to Ran. Our results suggest new targets for modulating Wnt signaling in disease states.