The connexin26 S17F mouse mutant represents a model for the human hereditary keratitis-ichthyosis-deafness syndrome

Abstract

Mutations in the GJB2 gene coding for connexin26 (Cx26) can cause a variety of deafness and hereditary hyperproliferative skin disorders in humans. In this study, we investigated the Cx26S17F mutation in mice, which had been identified to cause the keratitis-ichthyosis-deafness (KID) syndrome in humans. The KID syndrome is characterized by keratitis and chronic progressive corneal neovascularization, skin hyperplasia, sensorineural hearing loss and increased carcinogenic potential. We have generated a conditional mouse mutant, in which the floxed wild-type Cx26-coding DNA can be deleted and the Cx26S17F mutation is expressed under control of the endogenous Cx26 promoter. Homozygous mutants are not viable, whereas the surviving heterozygous mice show hyperplasia of tail and foot epidermis, wounded tails and annular tail restrictions, and are smaller than their wild-type littermates. Analyses of auditory brainstem responses (ABRs) indicate an ∼35 dB increased hearing threshold in these mice, which is likely due to the reduction of the endocochlear potential by 20-40%. Our results indicate that the Cx26S17F protein, which does not form functional gap junction channels or hemichannels, alters epidermal proliferation and differentiation in the heterozygous state. In the inner ear, reduced intercellular coupling by heteromeric channels composed of Cx26S17F and Cx30 could contribute to hearing impairment in heterozygous mice, while remaining wild-type Cx26 may be sufficient to stabilize Cx30 and partially maintain cochlear homeostasis. The phenotype of heterozygous mice resembles many of the symptoms of the human KID syndrome. Thus, these mice represent an appropriate model to further investigate the disease mechanism.

Connexin-Mediated Signaling in Nonsensory Cells Is Crucial for the Development of Sensory Inner Hair Cells in the Mouse Cochlea

“…These connexins have been shown to form extrajunctional hemichannels (Anselmi et al, 2008; Majumder et al, 2010) and also to coassemble to form homomeric or heteromeric gap junction channels between nonsensory cells (Forge et al, 2003; Martínez et al, 2009). This cell syncytium does not include the sensory IHCs or OHCs (e.g., Oesterle and Dallos, 1990; Jagger and Forge, 2006; Majumder et al, 2010), yet connexins have been shown to be crucial for hearing as deletion of Cx26 (e.g., Cohen-Salmon et al, 2002; Crispino et al, 2011) and mutation of Cx26 or Cx30 cause hearing loss in mice (Schütz et al, 2010, 2011) and humans (Wang et al, 2011; e.g., del Castillo and del Castillo, 2012). Deletion of Cx30 is normally associated with substantial downregulation of Cx26 expression in Cx30( −/− ) mice (Ortolano et al, 2008) as well as in DFNB1 patients (Lerer et al, 2001; Pallares-Ruiz et al, 2002; del Castillo et al, 2002; Rodriguez-Paris and Schrijver, 2009).…”

Connexin channels in congenital skin disorders

“…Transgenic mice expressing the Cx26-G45E and Cx26-S17F mutations have been generated, and both models develop features of KID syndrome [47, 48]. Cx26-G45E mice develop a severe lethal form of the disease, and significantly increased hemichannel activity was found to be present in primary keratinocytes derived from KID lesions [47].…”

Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases

“…For these mutations, inhibitor strategies may hold therapeutic value in addition to serving as research tools to pin down errors in channel gating and permselectivity (Figure 1). This concept is underscored by the topical accessibility of epidermal connexins and the fact that mouse models of Vohwinkel syndrome [28], EKV [29], ODDD [30], HED [31], and KID syndrome [32,33] already exist.…”