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.

• Authors: Melanie Schütz, Tanja Auth, Anna Gehrt, Felicitas Bosen, Inken Körber, Nicola Strenzke, Tobias Moser, Klaus Willecke
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 20 Issue 1 Pg. 28-39 (Jan 01 2011) ISSN: 1460-2083 [Electronic] England
• PMID: 20926451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Connexins
• GJB2 protein, human
• Gjb2 protein, mouse
• Ki-67 Antigen
• Proliferating Cell Nuclear Antigen
• Connexin 26

Topics

• Animals
• Connexin 26
• Connexins (genetics)
• Deafness (genetics)
• Disease Models, Animal
• Embryonic Stem Cells
• Evoked Potentials, Auditory, Brain Stem (genetics)
• Gene Expression Profiling
• Ichthyosis (genetics)
• Keratitis (genetics)
• Ki-67 Antigen (analysis)
• Mice
• Mice, Inbred C57BL
• Mutation
• Proliferating Cell Nuclear Antigen (analysis)
• Recombination, Genetic (genetics)