Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Abstract

Mutations in genes coding for connexin26 (Cx26) and/or Cx30 are linked to approximately half of all cases of human autosomal nonsyndromic prelingual deafness. Cx26 and Cx30 are the two major Cx isoforms found in the cochlea, and they coassemble to form hybrid (heteromeric and heterotypic) gap junctions (GJs). This molecular arrangement implies that homomeric GJs would remain in the cochlea if one of the coassembly partners were mutated resulting in null expression. We generated mice in which extra copies of the Cx26 gene were transgenically expressed from a modified bacterial artificial chromosome in a Cx30 ؊/؊ background. In the absence of the Cx30 gene, Cx26 expressed from extra alleles completely restored hearing sensitivity and prevented hair cell death in deaf Cx30 ؊/؊ mice. The results indicated that hybrid GJs consisting of Cx26 and Cx30 were not essential for normal hearing in mice and suggested that up-regulation of Cx26 or slowing down its protein degradation might be a therapeutic strategy to prevent and treat deafness caused by Cx30 mutations.gap junction ͉ hearing rescue ͉ hereditary deafness

Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear

“…A previous study reported Cx26 downregulation at the protein level in the cochlea, but not the liver, of Cx30 KO mice and suggested that the level of Cx26 mRNA in the cochlea of Cx30 KO mice was not significantly changed by Cx30 gene deletion (28). Interestingly, hearing has been restored in Cx30 KO mice independently from Cx30 by overexpressing Cx26 (28), although the use of a bacterial artificial chromosome system evades the regulatory control at the chromosome level.…”

“…Thus, the amount of Cx26 protein in liver cells of Cx32 KO mice is significantly lower than in controls (51); the Cx32 protein has been proposed to stabilize the amount of Cx26 in murine liver, where the two connexins form heteromeric channels (52). A previous study reported Cx26 downregulation at the protein level in the cochlea, but not the liver, of Cx30 KO mice and suggested that the level of Cx26 mRNA in the cochlea of Cx30 KO mice was not significantly changed by Cx30 gene deletion (28). Interestingly, hearing has been restored in Cx30 KO mice independently from Cx30 by overexpressing Cx26 (28), although the use of a bacterial artificial chromosome system evades the regulatory control at the chromosome level.…”

“…Recently, a potential coregulation of GJB2 and GJB6 has been postulated to underlie hearing loss in members of large kindred of German descent carrying a newly identified DFNB1 allele in trans with the 35delG allele of GJB2, resulting in dramatically reduced expression of both genes (27). A substantial decrease in Cx26 protein level (but not mRNA) was recently reported in cochlea of Cx30 KO mice (28).…”

“…Indeed, transgenic expression of extra copies of the Cx26 gene from a modified bacterial artificial chromosome in a Cx30 KO background restored cochlea development and hearing (28). Transcriptional regulation of connexin genes is altered during development as well as in several pathological conditions (31) and is related to ionic selectivity, distinct gating sensitivity to protein kinases, and selective permeability to second messengers (29).…”

Thérapie génique des surdités humaines

“…Des résultats encourageants ont été obtenus chez la souris. L'audition des souris défectueuses pour la connexine 30 a été partiellement rétablie en surexprimant le gène codant pour la connexine 26 [29]. Plus récemment, une restauration de l'audition a été obtenue chez les souris homozygotes mutantes dépourvues du transporteur vésiculaire du glutamate VGLUT3.…”