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

Fatima Rouan, Thomas W. White, Nkecha Brown, Aileen M. Taylor, Thomas W. Lucke, David L. Paul, Colin S. Munro, Jouni Uitto, Malcolm B. Hodgins

Research output: Contribution to journalArticle

Abstract

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 (DE42) in Cx26. To dissect the pathomechanisms that result in diverse phenotypes of dominant GJB2 mutations, we studied the effect of three Cx26 mutants (DE42, 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

Original languageEnglish
Pages (from-to)2105-2113
Number of pages9
JournalJournal of Cell Science
Volume114
Issue number11
Publication statusPublished - 1 Jun 2001

Fingerprint

Connexin 43
Connexins
Hearing Loss
Phenotype
Mutation
Palmoplantar Keratoderma
Connexin 26
Xenopus
Constriction
Oocytes
Amino Acids
Skin

Keywords

  • connexins
  • gap junctions
  • deafness
  • epidermal differentiation
  • skin disorder

Cite this

Rouan, F., White, T. W., Brown, N., Taylor, A. M., Lucke, T. W., Paul, D. L., ... Hodgins, M. B. (2001). Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. Journal of Cell Science, 114(11), 2105-2113.
Rouan, Fatima ; White, Thomas W. ; Brown, Nkecha ; Taylor, Aileen M. ; Lucke, Thomas W. ; Paul, David L. ; Munro, Colin S. ; Uitto, Jouni ; Hodgins, Malcolm B. / Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. In: Journal of Cell Science. 2001 ; Vol. 114, No. 11. pp. 2105-2113.
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Rouan, F, White, TW, Brown, N, Taylor, AM, Lucke, TW, Paul, DL, Munro, CS, Uitto, J & Hodgins, MB 2001, 'Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation', Journal of Cell Science, vol. 114, no. 11, pp. 2105-2113.

Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. / Rouan, Fatima; White, Thomas W.; Brown, Nkecha; Taylor, Aileen M.; Lucke, Thomas W.; Paul, David L.; Munro, Colin S.; Uitto, Jouni; Hodgins, Malcolm B.

In: Journal of Cell Science, Vol. 114, No. 11, 01.06.2001, p. 2105-2113.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation

AU - Rouan, Fatima

AU - White, Thomas W.

AU - Brown, Nkecha

AU - Taylor, Aileen M.

AU - Lucke, Thomas W.

AU - Paul, David L.

AU - Munro, Colin S.

AU - Uitto, Jouni

AU - Hodgins, Malcolm B.

N1 - <p>Originally published in: Journal of Cell Science (2001), 114 (11), pp.2105-2113.</p>

PY - 2001/6/1

Y1 - 2001/6/1

N2 - 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 (DE42) in Cx26. To dissect the pathomechanisms that result in diverse phenotypes of dominant GJB2 mutations, we studied the effect of three Cx26 mutants (DE42, 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

AB - 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 (DE42) in Cx26. To dissect the pathomechanisms that result in diverse phenotypes of dominant GJB2 mutations, we studied the effect of three Cx26 mutants (DE42, 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

KW - connexins

KW - gap junctions

KW - deafness

KW - epidermal differentiation

KW - skin disorder

M3 - Article

VL - 114

SP - 2105

EP - 2113

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 11

ER -