title: Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.
abstract: Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.|Department of Human Molecular Genetics and Biochemistry, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Alon
authors.identifier: http://orcid.org/0000-0001-6158-1089
authors.initials: A
authors.lastname: Peled
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Sarig
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.|Division of Dermatology, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Liat
authors.initials: L
authors.lastname: Samuelov
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Bertolini
authors.affiliation: Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Limor
authors.identifier: http://orcid.org/0000-0001-8169-9623
authors.initials: L
authors.lastname: Ziv
authors.affiliation: Department of Cell and Developmental Biology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.|Department of Human Molecular Genetics and Biochemistry, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Eskin-Schwartz
authors.affiliation: Division of Dermatology, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Christopher A
authors.identifier: http://orcid.org/0000-0002-3794-4289
authors.initials: CA
authors.lastname: Adase
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Natalia
authors.initials: N
authors.lastname: Malchin
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Bochner
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Gilad
authors.initials: G
authors.lastname: Fainberg
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldberg
authors.affiliation: Department of Dermatology, Osaka City University, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sugawara
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.
authors.forename: Avital
authors.identifier: http://orcid.org/0000-0003-1364-561X
authors.initials: A
authors.lastname: Baniel
authors.affiliation: Department of Dermatology, Osaka City University, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuruta
authors.affiliation: Department of Cell and Developmental Biology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Chen
authors.identifier: http://orcid.org/0000-0002-7801-3499
authors.initials: C
authors.lastname: Luxenburg
authors.affiliation: Faculty of Chemistry, Technion, Haifa, Israel.
authors.forename: Noam
authors.identifier: http://orcid.org/0000-0003-2766-8409
authors.initials: N
authors.lastname: Adir
authors.affiliation: Laboratory of Skin Biology, National Institute of Health, Bethesda, Maryland, United States of America.
authors.forename: Olivier
authors.identifier: http://orcid.org/0000-0003-3200-1019
authors.initials: O
authors.lastname: Duverger
authors.affiliation: Laboratory of Skin Biology, National Institute of Health, Bethesda, Maryland, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Morasso
authors.affiliation: Institute of Human Genetics, Haemek Medical Center, Afula, Israel.|Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.affiliation: Division of Dermatology, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.affiliation: Department of Cell and Developmental Biology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany.|Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
authors.affiliation: Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel.|Department of Human Molecular Genetics and Biochemistry, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology; D016368:Frameshift Mutation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018859:Hair Follicle / Q000254:growth & development; D006801:Humans; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014070:Tooth / Q000254:growth & development / Q000378:metabolism
chemical_list: C497762:Notch1 protein, mouse; D011506:Proteins; D051881:Receptor, Notch1; C576748:TSPEAR protein, human