title: Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.
abstract: Keratitis-ichthyosis-deafness syndrome (KID) is a rare ectodermal dysplasia characterized by vascularizing keratitis, profound sensorineural hearing loss (SNHL), and progressive erythrokeratoderma, a clinical triad that indicates a failure in development and differentiation of multiple stratifying epithelia. Here, we provide compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2. In each of 10 patients with KID, we identified a point mutation leading to substitution of conserved residues in the cytoplasmic amino terminus or first extracellular domain of Cx26. One of these mutations was detected in six unrelated sporadic case subjects and also segregated in one family with vertical transmission of KID. These results indicate the presence of a common, recurrent mutation and establish its autosomal dominant nature. Cx26 and the closely related Cx30 showed differential expression in epidermal, adnexal, and corneal epithelia but were not significantly altered in lesional skin. However, mutant Cx26 was incapable of inducing intercellular coupling in vitro, which indicates its functional impairment. Our data reveal striking genotype-phenotype correlations and demonstrate that dominant GJB2 mutations can disturb the gap junction system of one or several ectodermal epithelia, thereby producing multiple phenotypes: nonsyndromic SNHL, syndromic SNHL with palmoplantar keratoderma, and KID. Decreased host defense and increased carcinogenic potential in KID illustrate that gap junction communication plays not only a crucial role in epithelial homeostasis and differentiation but also in immune response and epidermal carcinogenesis.
authors.affiliation: Department of Dermatology and Cutaneous Biology and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. gabriele.richard@mail.tju.edu
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: Fatima
authors.initials: F
authors.lastname: Rouan
authors.forename: Colin E
authors.initials: CE
authors.lastname: Willoughby
authors.forename: Nkecha
authors.initials: N
authors.lastname: Brown
authors.forename: Pil
authors.initials: P
authors.lastname: Chung
authors.forename: Markku
authors.initials: M
authors.lastname: Ryynänen
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.forename: Sherri J
authors.initials: SJ
authors.lastname: Bale
authors.forename: John J
authors.initials: JJ
authors.lastname: DiGiovanna
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Laura
authors.initials: L
authors.lastname: Russell
mesh_terms: D001483:Base Sequence; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D003315:Cornea / Q000378:metabolism / Q000473:pathology; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007634:Keratitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D021381:Protein Transport; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013577:Syndrome
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26