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
Blepharocheilodontic (BCD) syndrome is a rare condition characterized by bilateral cleft lip and palate (BCLP), eyelid abnormalities, and oligodontia. Despite orofacial clefting and oligodontia being central features of the condition, detailed reports of dental and craniofacial characteristics are scarce. The aim of this study was to analyze the dental and craniofacial features in a group of patients with BCD syndrome (three of which were related). Cephalometric radiographic analyses were performed on BCD syndrome patients (all radiographs taken at age 8 years) and compared to 40 randomly selected age-matched controls (20 non-syndromic BCLP, 20 non-cleft). Also, we assessed clinical records, photographs, dental study casts, and dental radiographs to determine the extent and pattern of tooth agenesis, dental morphology and malocclusion. BCD syndrome patients showed a very severe skeletal III malocclusion (maxillary-mandibular sagittal discrepancy) and reduced anterior lower face measurement compared to non-syndromic BCLP and non-cleft controls (P = 0.001, P = 0.027). All patients exhibited oligodontia (mean number of missing permanent teeth 13.7, range 7-17). All patients exhibited missing upper central and lateral incisor, upper canine and premolar teeth. Variations in dental morphology included taurodontism, conical-shaped teeth, and notching of the incisal edges. All patients had a short and narrow maxilla which translated into anterior and posterior cross bites. We conclude that, in our BCD syndrome group, the craniofacial skeletal defects are more severe than patients with BCLP. The pattern of tooth agenesis is unusual as it included teeth that are normally highly resistant to agenesis, namely upper central incisor and canine teeth. © 2017 Wiley Periodicals, Inc.