Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation

被引:0
|
作者
Rouan, F
White, TW
Brown, N
Taylor, AV
Lucke, TW
Paul, DL
Munro, CS
Uitto, J
Hodgins, MB
Richard, G [1 ]
机构
[1] Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA
[3] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA
[4] Royal Victoria Infirm, Dept Dermatol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England
[5] So Gen Hosp, Dept Dermatol, Glasgow G51 4TF, Lanark, Scotland
[6] Univ Glasgow, Dept Dermatol, Glasgow G12 8QQ, Lanark, Scotland
关键词
connexins; gap junctions; deafness; skin disorder; epidermal differentiation;
D O I
暂无
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 (Delta E42) in Cx26. To dissect the pathomechanisms that result in diverse phenotypes of dominant GJB2 mutations, we studied the effect of three Cx26 mutants (Delta E42, 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<0.05) inhibited intercellular conductance of co-expressed wtCx43, indicating a direct interaction of mutant Cx26 units with wtCx43. These results demonstrate, for the first time, a trans-dominant negative effect of Cx26 mutants in vitro. Furthermore, they support a novel concept suggesting that the principal mechanism for manifestation of dominant GJB2 mutations in the skin is their dominant interference with the function of wtCx43. This assumption is further corroborated by our finding that Cx26 and Cx43 focally colocalize at gap junctional plaques in affected skin tissue of two carriers of <Delta>E42.
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页码:2105 / 2113
页数:9
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