trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation
| Autor: | Jouni Uitto, Colin S. Munro, Aileen Taylor, David L. Paul, Fatima Rouan, Thomas W. White, Thomas W. Lucke, Gabriela Richard, Malcolm B. Hodgins, Nkecha Brown |
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| Rok vydání: | 2001 |
| Předmět: |
Adult
Male Adolescent Cellular differentiation DNA Mutational Analysis Mutant Xenopus Connexin Deafness Biology medicine.disease_cause Connexins Xenopus laevis Keratoderma Palmoplantar otorhinolaryngologic diseases medicine Animals Humans Child Gene Genes Dominant Genetics Mutation Base Sequence Gap junction Cell Differentiation Cell Biology Middle Aged biology.organism_classification Phenotype Pedigree Cell biology Connexin 26 Electrophysiology Child Preschool Connexin 43 Oocytes Female Epidermis |
| Zdroj: | Journal of Cell Science. 114:2105-2113 |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.114.11.2105 |
| Popis: | Dominant mutations of GJB2-encoding connexin-26 (Cx26) have pleiotropic effects, causing either hearing impairment (HI) alone or in association with palmoplantar keratoderma (PPK/HI). We examined a British family with the latter phenotype and identified a new dominant GJB2 mutation predicted to eliminate the amino acid residue E42 (ΔE42) in Cx26. To dissect the pathomechanisms that result in diverse phenotypes of dominant GJB2 mutations, we studied the effect of three Cx26 mutants (ΔE42, D66H and R75W) identified in individuals with PPK/HI, and another (W44C) present in individuals with non-syndromic HI on gap junctional intercellular communication. We expressed mutant Cx26 alone and together with the epidermal connexins Cx26, Cx37 and Cx43 in paired Xenopus oocytes, and measured the intercellular coupling by dual voltage clamping. Homotypic expression of each connexin as well as co-expression of wild-type (wt) Cx26/wtCx43 and wtCx26/wtCx37 yielded variable, yet robust, levels of channel activity. However, all four Cx26 mutants were functionally impaired and failed to induce intercellular coupling. When co-expressed with wtCx26, all four mutants suppressed the wtCx26 channel activity consistent with a dominant inhibitory effect. However, only those Cx26 mutants associated with a skin phenotype also significantly (P |
| Databáze: | OpenAIRE |
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