Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis

Alon Peled, Ofer Sarig, Liat Samuelov, Marta Bertolini, Limor Ziv, Daphna Weissglas-Volkov, Marina Eskin-Schwartz, Christopher A. Adase, Natalia Malchin, Ron Bochner, Gilad Fainberg, Ilan Goldberg, Koji Sugawara, Avital Baniel, Daisuke Tsuruta, Chen Luxenburg, Noam Adir, Olivier Duverger, Maria Morasso, Stavit ShalevRichard L. Gallo, Noam Shomron, Ralf Paus, Eli Sprecher

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1006369
JournalPLoS Genetics
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Fingerprint

hair follicles
Hair Follicle
morphogenesis
Scalp
Morphogenesis
hair
Hair
hairs
tooth
mutation
Tooth
teeth
Hypotrichosis
Anodontia
Exome
Ectodermal Dysplasia
Thrombospondins
Mutation
missense mutation
laminin

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Peled, A., Sarig, O., Samuelov, L., Bertolini, M., Ziv, L., Weissglas-Volkov, D., ... Sprecher, E. (2016). Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis. PLoS Genetics, 12(10), [e1006369]. https://doi.org/10.1371/journal.pgen.1006369

Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis. / Peled, Alon; Sarig, Ofer; Samuelov, Liat; Bertolini, Marta; Ziv, Limor; Weissglas-Volkov, Daphna; Eskin-Schwartz, Marina; Adase, Christopher A.; Malchin, Natalia; Bochner, Ron; Fainberg, Gilad; Goldberg, Ilan; Sugawara, Koji; Baniel, Avital; Tsuruta, Daisuke; Luxenburg, Chen; Adir, Noam; Duverger, Olivier; Morasso, Maria; Shalev, Stavit; Gallo, Richard L.; Shomron, Noam; Paus, Ralf; Sprecher, Eli.

In: PLoS Genetics, Vol. 12, No. 10, e1006369, 01.10.2016.

Research output: Contribution to journalArticle

Peled, A, Sarig, O, Samuelov, L, Bertolini, M, Ziv, L, Weissglas-Volkov, D, Eskin-Schwartz, M, Adase, CA, Malchin, N, Bochner, R, Fainberg, G, Goldberg, I, Sugawara, K, Baniel, A, Tsuruta, D, Luxenburg, C, Adir, N, Duverger, O, Morasso, M, Shalev, S, Gallo, RL, Shomron, N, Paus, R & Sprecher, E 2016, 'Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis', PLoS Genetics, vol. 12, no. 10, e1006369. https://doi.org/10.1371/journal.pgen.1006369
Peled A, Sarig O, Samuelov L, Bertolini M, Ziv L, Weissglas-Volkov D et al. Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis. PLoS Genetics. 2016 Oct 1;12(10). e1006369. https://doi.org/10.1371/journal.pgen.1006369
Peled, Alon ; Sarig, Ofer ; Samuelov, Liat ; Bertolini, Marta ; Ziv, Limor ; Weissglas-Volkov, Daphna ; Eskin-Schwartz, Marina ; Adase, Christopher A. ; Malchin, Natalia ; Bochner, Ron ; Fainberg, Gilad ; Goldberg, Ilan ; Sugawara, Koji ; Baniel, Avital ; Tsuruta, Daisuke ; Luxenburg, Chen ; Adir, Noam ; Duverger, Olivier ; Morasso, Maria ; Shalev, Stavit ; Gallo, Richard L. ; Shomron, Noam ; Paus, Ralf ; Sprecher, Eli. / Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis. In: PLoS Genetics. 2016 ; Vol. 12, No. 10.
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AU - Eskin-Schwartz, Marina

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AU - Sugawara, Koji

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AU - Morasso, Maria

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