title: GJB6, of which mutations underlie Clouston syndrome, is a potential direct target gene of p63.
abstract: BACKGROUND
  Clouston syndrome is a rare autosomal dominant condition characterized by hypotrichosis, nail dystrophy, and occasionally palmoplantar keratoderma. The disease is caused by mutations in GJB6 gene, which encodes a gap junction protein connexin 30 (Cx30).
  
  
  OBJECTIVE
  To disclose the molecular basis of Clouston syndrome in a Lebanese-German family, and also to determine precise expression of Cx30 in normal skin of humans and mice, as well as transcriptional regulation for the GJB6 expression.
  
  
  METHODS
  We searched for mutations in the GJB6 gene using DNA of the family members with Clouston syndrome. We performed immunostaining to localize the Cx30 expression in normal human skin and mouse embryos. In addition, we did a series of in vitro studies to investigate if the GJB6 could be a direct transcriptional target gene of p63.
  
  
  RESULTS
  We identified a recurrent heterozygous mutation c.31G>C (p.Gly11Arg) in the GJB6 gene in the Lebanese-German family with Clouston syndrome. Immunostaining in normal human skin sections demonstrated predominant expression of Cx30 in hair follicles, nails, and palmoplantar epidermis, which partially overlapped with p63 expression. We also showed co-expression of Cx30 and p63 in developing mouse hair follicles and nail units. In cultured cells, the GJB6 expression was significantly upregulated by ΔNp63α isoform. Further in vitro analyses suggested that ΔNp63α was potentially involved in the GJB6 expression via binding to the sequences in intron 1 of the GJB6 gene.
  
  
  CONCLUSIONS
  Our data further underscore the crucial roles of Cx30 in morphogenesis and development of skin and its appendages.
authors.affiliation: Laboratory of Genetic Skin Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujimoto
authors.forename: Mazen
authors.initials: M
authors.lastname: Kurban
authors.forename: Motonobu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Muhammad
authors.initials: M
authors.lastname: Farooq
authors.forename: Hiroki
authors.initials: H
authors.lastname: Fujikawa
authors.forename: Abdul-Ghani
authors.initials: AG
authors.lastname: Kibbi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.forename: Maurice
authors.initials: M
authors.lastname: Dahdah
authors.forename: Mona
authors.initials: M
authors.lastname: Matta
authors.forename: Hassan
authors.initials: H
authors.lastname: Diab
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
mesh_terms: D000328:Adult; D000818:Animals; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics / Q000378:metabolism; D007223:Infant; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense / Q000235:genetics; D009260:Nail Diseases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: C081876:CKAP4 protein, human; D000075302:Connexin 30; D017630:Connexins; C491020:GJB6 protein, human; C100629:Gjb6 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; C486419:Trp63 protein, mouse