2. Academic Validation
  3. Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1

Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1

  • Genet Med. 2017 Sep;19(9):1013-1021. doi: 10.1038/gim.2017.11.
Jamal Ghoumid 1 2 3,  Morgane Stichelbout 1 2,  Anne-Sophie Jourdain 2 4,  Frederic Frenois 1 2,  Sophie Lejeune-Dumoulin 1,  Marie-Pierre Alex-Cordier 5,  Marine Lebrun 6,  Pierre Guerreschi 2 3 7,  Veronique Duquennoy-Martinot 2 3 7,  Matthieu Vinchon 2 3 8,  Joel Ferri 3 9,  Matthieu Jung 10,  Serge Vicaire 10,  Clemence Vanlerberghe 1 2 3,  Fabienne Escande 2 4,  Florence Petit 1 2 3,  Sylvie Manouvrier-Hanu 1 2 3
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.
  • 2 EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.
  • 3 Lille University School of Medicine, Lille 2 University, Lille, France.
  • 4 Department of Biochemistry and Molecular Biology, Lille University Hospital, CHU Lille, Lille, France.
  • 5 Department of Medical Genetics, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, and Eastern Biology and Pathology Centre, Bron, France.
  • 6 Department of Medical Genetics, St Etienne University Hospital, Saint Priez en Jarez, France.
  • 7 Department of Plastic, Reconstructive and Aesthetic Surgery, Lille University Hospital, CHU Lille, Lille, France.
  • 8 Department of Pediatric Neurosurgery, Lille University Hospital, CHU Lille, Lille, France.
  • 9 Department of Oral and Maxillofacial, Lille University Hospital, CHU Lille, Lille, France.
  • 10 IGBMC Microarray and Sequencing Platform, Illkirch, France.
PMID: 28301459 DOI: 10.1038/gim.2017.11
Abstract

Purpose: Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown.

Methods: We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families.

Results: We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation.

Conclusion: Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric Cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.

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