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Assembly of the cochlear gap junction macromolecular complex requires connexin 26
Assembly of the cochlear gap junction macromolecular complex requires connexin 26
- Source :
- Journal of Clinical Investigation. 124:1598-1607
- Publication Year :
- 2014
- Publisher :
- American Society for Clinical Investigation, 2014.
-
Abstract
- Hereditary deafness affects approximately 1 in 2,000 children. Mutations in the gene encoding the cochlear gap junction protein connexin 26 (CX26) cause prelingual, nonsyndromic deafness and are responsible for as many as 50% of hereditary deafness cases in certain populations. Connexin-associated deafness is thought to be the result of defective development of auditory sensory epithelium due to connexion dysfunction. Surprisingly, CX26 deficiency is not compensated for by the closely related connexin CX30, which is abundantly expressed in the same cochlear cells. Here, using two mouse models of CX26-associated deafness, we demonstrate that disruption of the CX26-dependent gap junction plaque (GJP) is the earliest observable change during embryonic development of mice with connexin-associated deafness. Loss of CX26 resulted in a drastic reduction in the GJP area and protein level and was associated with excessive endocytosis with increased expression of caveolin 1 and caveolin 2. Furthermore, expression of deafness-associated CX26 and CX30 in cell culture resulted in visible disruption of GJPs and loss of function. Our results demonstrate that deafness-associated mutations in CX26 induce the macromolecular degradation of large gap junction complexes accompanied by an increase in caveolar structures.
- Subjects :
- Caveolin 2
Hearing Loss, Sensorineural
Caveolin 1
Connexin
Mice, Transgenic
Biology
medicine.disease_cause
Connexins
Mice
otorhinolaryngologic diseases
medicine
Animals
Humans
Nonsyndromic deafness
Loss function
Cochlea
Mice, Knockout
Genetics
Mutation
Gap junction
Gap Junctions
General Medicine
medicine.disease
Endocytosis
Mice, Mutant Strains
Cell biology
Connexin 26
Mice, Inbred C57BL
Disease Models, Animal
Multiprotein Complexes
Proteolysis
Research Article
Subjects
Details
- ISSN :
- 00219738
- Volume :
- 124
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....c32156ab7f7818c7dc0f61ae6f5bf402
- Full Text :
- https://doi.org/10.1172/jci67621