title: Mutations in GRHL2 result in an autosomal-recessive ectodermal Dysplasia syndrome.
abstract: Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease.
authors.affiliation: St. John's Institute of Dermatology, King's College London, Guy's Campus, London SE1 9RT, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Petrof
authors.affiliation: As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City 13001, Kuwait.
authors.forename: Arti
authors.initials: A
authors.lastname: Nanda
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 9RT, UK.
authors.forename: Jake
authors.initials: J
authors.lastname: Howden
authors.affiliation: St. John's Institute of Dermatology, King's College London, Guy's Campus, London SE1 9RT, UK; Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Takeichi
authors.affiliation: National Diagnostic Epidermolysis Bullosa Laboratory, Viapath, St. Thomas' Hospital, London SE1 7EH, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.affiliation: National Diagnostic Epidermolysis Bullosa Laboratory, Viapath, St. Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Sophia
authors.initials: S
authors.lastname: Aristodemou
authors.affiliation: National Diagnostic Epidermolysis Bullosa Laboratory, Viapath, St. Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Ozoemena
authors.affiliation: National Diagnostic Epidermolysis Bullosa Laboratory, Viapath, St. Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.affiliation: Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Celine
authors.initials: C
authors.lastname: Pourreyron
authors.affiliation: Department of Genetics, Development, and Molecular Biology, School of Biology, Aristotle University, Thessaloniki 54124, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dafou
authors.affiliation: St. John's Institute of Dermatology, King's College London, Guy's Campus, London SE1 9RT, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Proudfoot
authors.affiliation: As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City 13001, Kuwait.
authors.forename: Hejab
authors.initials: H
authors.lastname: Al-Ajmi
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.affiliation: Department of Medical and Molecular Genetics, King's College London School of Medicine and Guy's Hospital, London SE1 9RT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 9RT, UK.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: St. John's Institute of Dermatology, King's College London, Guy's Campus, London SE1 9RT, UK; Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee DD1 5EH, UK. Electronic address: john.mcgrath@kcl.ac.uk.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D015153:Blotting, Western; D002648:Child; D002972:Cleft Palate / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D013576:Syndactyly / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors