Nectin-4 mutations causing ectodermal dysplasia with syndactyly perturb the rac1 pathway and the kinetics of adherens junction formation

Paola Fortugno, Emmanuelle Josselin, Konstantinos Tsiakas, Emanuele Agolini, Gianluca Cestra, Massimo Teson, René Santer, Daniele Castiglia, Giuseppe Novelli, Bruno Dallapiccola, Ingo Kurth, Marc Lopez, Giovanna Zambruno, Francesco Brancati

Research output: Contribution to journalArticlepeer-review


Defective nectin-1 and-4 have been implicated in ectodermal dysplasia (ED) syndromes with variably associated features including orofacial and limb defects. In particular, nectin-1 mutations cause cleft lip/palate ED (CLPED1; OMIM#225060), whereas defective nectin-4 is associated with ED-syndactyly syndrome (EDSS1; OMIM#613573). Although the broad phenotypic overlap suggests a common mode of action of nectin-1 and-4, little is known about the pathogenic mechanisms involved. We report the identification of, to our knowledge, a previously undescribed nectin-4 homozygous p.Val242Met missense mutation in a patient with EDSS1. We used patient skin biopsy and primary keratinocytes, as well as nectin-4 ectopic expression in epithelial cell lines, to characterize functional consequences of p.Val242Met and p.Thr185Met mutations, the latter previously identified in compound heterozygosity with a truncating mutation. We show that nectin-4-altered expression perturbs nectin-1 clustering at keratinocyte contact sites and delays, but does not impede cell-cell aggregation and cadherin recruitment at adherens junctions (AJs). Moreover, trans-interaction of nectin-1 and-4 induces the activation of Rac1, a member of the Rho family of small GTPases, and regulates E-cadherin-mediated cell-cell adhesion. These data outline a synergistic action of nectin-1 and-4 in the early steps of AJ formation and implicate this interaction in modulating the Rac1 signaling pathway.

Original languageEnglish
Pages (from-to)2146-2153
Number of pages8
JournalJournal of Investigative Dermatology
Issue number8
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology


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