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.

Ophthalmological screening of a paediatric cochlear implant population: a retrospective analysis and 12-year follow-up

“…Rarely, autosomal dominant CX26 mutations may result in Keratitis-Ichthyosis-Deafness (KID) syndrome characterized by congenital hearing loss associated with skin lesions and vascularizing keratitis. 36 Approximately 15-30% of hereditary hearing impairment involves other organ systems and occurs as a syndrome. In addition, abnormal ocular findings are associated with certain common deafness syndromes.…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…However, the majority of the participants thought that the inclusion of EKV into this classification is appropriate and useful and in accordance with the inclusion of KID (keratitiseichthyosisedeafness) syndrome 118,119 (Fig 5, C ), which is identical to ichthyosis hystrix type Rheydt 120 or hystrixlike ichthyosis deafness syndrome. 3 KID syndrome is caused by heterozygous mutations in GJB2 (connexin 26) 121 and patients with congenital presentation in particular have generalized skin involvement. In some cases, it may overlap with Clouston syndrome, which is caused by mutations in GJB6 (connexin 30).…”

Mathematical model of morphogen electrophoresis through gap junctions

“…Several human syndromes have been identified as mutations in connexin genes (Maestrini et al, 1999;Richard et al, 2002), and transgenic mice are beginning to allow the molecular dissection of gap junctional communication (GJC) function in these contexts (Krutovskikh and Yamasaki, 2000), including the spread of electric waves in cardiac tissue (Kimura et al, 1995;Severs, 1999) and the brain (Budd and Lipton, 1998;Momose-Sato et al, 2003, and the propagation of signals through gland cells to synchronize hormonal action and secretion (Meda, 1996). Regulation of tumor (Loewenstein and Rose, 1992;Yamasaki et al, 1995;Krutovskikh and Yamasaki, 1997;Li and Herlyn, 2000;Omori et al, 2001) and stem cell (Trosko et al, 2000;Burnside and Collas, 2002;Tazuke et al, 2002;Gilboa et al, 2003;Cai et al, 2004;Wong et al, 2004) …”