Nectin-4 Mutations Causing Ectodermal Dysplasia with Syndactyly Perturb the Rac1 Pathway and the Kinetics of Adherens Junction Formation

• DOI: 10.1038/jid.2014.119
• Publication Date: 2014-02-27T14:51:38Z
• Authors: 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
• Keywords: rac1 GTP-Binding Protein; 0301 basic medicine; 571; Adherens Junctions; Animals; Cell Adhesion; Cell Adhesion Molecules; Cell Aggregation; Cells, Cultured; Dogs; Ectodermal Dysplasia; Humans; Kinetics; Signal Transduction; Syndactyly; rac1 GTP-Binding Protein; Mutation; 2708; Biochemistry; Cell Biology; Molecular Biology; Nectins; Dermatology; Settore MED/03 - GENETICA MEDICA; Biochemistry; 03 medical and health sciences; Dogs; Ectodermal Dysplasia; Cell Adhesion; Animals; Humans; Molecular Biology; Cells, Cultured; Cell Aggregation; Adherens Junctions; Animals; Cell Adhesion; Cell Adhesion Molecules; Cell Aggregation; Cells; Cultured; Dogs; Ectodermal Dysplasia; Humans; Kinetics; Signal Transduction; Syndactyly; rac1 GTP-Binding Protein; Mutation; 2708; Biochemistry; Cell Biology; Molecular Biology; Cell Biology; Adherens Junctions; Kinetics; Mutation; Syndactyly; Cell Adhesion Molecules; Signal Transduction

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.