Variants in members of the cadherin–catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome

Anneke Kievit, Federico Tessadori, Hannie Douben, Ingrid Jordens, Madelon Maurice, Jeannette Hoogeboom, Raoul Hennekam, Sheela Nampoothiri, Hülya Kayserili, Marco Castori, Margo Whiteford, Connie Motter, Catherine Melver, Michael Cunningham, Anne Hing, Nancy M. Kokitsu-Nakata, Siulan Vendramini-Pittoli, Antonio Richieri-Costa, Annette F. Baas, Corstiaan C. BreugemKaren Duran, Maarten Massink, Patrick W.B. Derksen, Wilfred F.J. van IJcken, Leontine van Unen, Fernando Santos-Simarro, Pablo Lapunzina, Vera L. Gil-da Silva Lopes, Elaine Lustosa-Mendes, Max Krall, Anne Slavotinek, Victor Martinez-Glez, Jeroen Bakkers, Koen L.I. van Gassen, Annelies de Klein, M. J.H. van Den Boogaard, Gijs van Haaften

Research output: Contribution to journalArticle

Abstract

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin–catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin–catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalEuropean Journal of Human Genetics
DOIs
Publication statusAccepted/In press - Jan 18 2018

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Kievit, A., Tessadori, F., Douben, H., Jordens, I., Maurice, M., Hoogeboom, J., Hennekam, R., Nampoothiri, S., Kayserili, H., Castori, M., Whiteford, M., Motter, C., Melver, C., Cunningham, M., Hing, A., Kokitsu-Nakata, N. M., Vendramini-Pittoli, S., Richieri-Costa, A., Baas, A. F., ... van Haaften, G. (Accepted/In press). Variants in members of the cadherin–catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome. European Journal of Human Genetics, 1-10. https://doi.org/10.1038/s41431-017-0010-5