title: Nectin-4 mutations causing ectodermal dysplasia with syndactyly perturb the rac1 pathway and the kinetics of adherens junction formation.
abstract: 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.
authors.affiliation: Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fortugno
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille University, Marseille, France; Inserm-U1068 (Laboratoire d'Oncologie Moléculaire), CNRS-UMR7258, Marseille, France; Institut Paoli-Calmettes, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Josselin
authors.affiliation: Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsiakas
authors.affiliation: Mendel Laboratory, Casa Sollievo Della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Agolini
authors.affiliation: IBPM, Consiglio Nazionale delle Ricerche, c/o Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Cestra
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Teson
authors.affiliation: Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Castiglia
authors.affiliation: Genetics Section, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.affiliation: Department of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille University, Marseille, France; Inserm-U1068 (Laboratoire d'Oncologie Moléculaire), CNRS-UMR7258, Marseille, France; Institut Paoli-Calmettes, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lopez
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, Gabriele D'Annunzio University of Chieti-Pescara, Chieti, Italy; Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Rome, Italy. Electronic address: f.brancati@igenetica.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
mesh_terms: D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002449:Cell Aggregation; D002478:Cells, Cultured; D004285:Dogs; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D009154:Mutation; D000075983:Nectins; D015398:Signal Transduction / Q000502:physiology*; D013576:Syndactyly / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; D000075983:Nectins; C107953:RAC1 protein, human; C442228:NECTIN4 protein, human; D020830:rac1 GTP-Binding Protein