Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential

Abstract

The gap junction protein connexin30 (Cx30) is expressed in a variety of tissues that include epithelial and mesenchymal structures of the inner ear. We generated Cx30 (Gjb6) deficient mice by deletion of the Cx30 coding region. Homozygous mutants (Cx30((-/-))) were born at the expected Mendelian frequency, developed normally and were fertile. However, they exhibit a severe constitutive hearing impairment. From the age of hearing onset, these mice lack the electrical potential difference between the endolymphatic and perilymphatic compartments of the cochlea, i.e. the endocochlear potential, which plays a key role in the high sensitivity of the mammalian auditory organ. In addition, after postnatal day 18, the cochlear sensory epithelium starts to degenerate by cell apoptosis. This degeneration process is likely to account for the concomitant decrease of the endolymphatic potassium concentration and the aggravation of the hearing loss in adult Cx30((-/-)) mice. The Cx30 ((-/-)) phenotype thus reveals the critical role of Cx30 both in generating the endocochlear potential and for survival of the auditory hair cells after the onset of hearing. The Cx30 deficient mice may represent a valuable model to study the mechanism of the hearing loss in human patients carrying a homozygous deletion of the CX30 gene (del Castillo et al., 2002, New Engl. J. Med., 346, 243-249).

The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering

“…Mutations in the Cx26 and Cx30 genes are a common cause of autosomal recessive non-syndromic deafness in humans (Nickel and Forge 2008). In mouse models, the deletion of Cx26 or Cx30 from epithelial cells results in hair cell death (CohenSalmon et al 2002;Teubner et al 2003). Our dye transfer experiments here showed that the gap junctions between root cells were permeable to Lucifer yellow, a large and negatively charged dye molecule.…”

The 342-kb deletion inGJB6is not present in patients with non-syndromic hearing loss from Austria

“…Digenic inheritance in those cases is supported by the findings that both genes, GJB2 and GJB6, encode for gap junction proteins, connexin 26 and connexin 30, respectively, and are expressed in the same cells in the rat cochlea and in the cochlea of the 22-week-old human embryo (Lautermann et al, 1999). Likewise, mice mutants that are homozygous for a deletion of the GJB6 coding region develop NSHL (Teubner et al, 2003) representing a mouse model for this type of HL.…”

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…The location of these proteins along the membranes of the different cells of the adult stria vascularis is depicted in Figure 1(B). Disrupting the function of any of these proteins (including connexin proteins) in the stria vascularis or at other locations in the cochlea where they are thought to be involved in K + homeostasis results in immediate SNHL (Cohen‐Salmon et al, 2002; Teubner et al, 2003; Nin et al, 2008). In many cases of both syndromic (as mentioned above) and nonsyndromic SNHL, the endocochlear potential is likely to be affected.…”

“…Although less frequent, mutations in GJB6 ( CX30 ) (Grifa et al, 1999; del Castillo et al, 2002) and GJA1 (CX43) (Liu et al, 2001; Hong et al, 2010) have also been linked to SNHL. These gap junction proteins are thought to play a role in maintaining cochlear ion homeostasis and the endocochlear potential, as shown in Gjb6 ‐deficient mice (Teubner et al, 2003), by passively recycling K + ions back to the stria vascularis. The observed expression in the developing human cochlea is in support of this model.…”