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

¹ Department of Dermatology and Cutaneous Biology, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
² Department of Neurobiology, Harvard Medical School, Boston, MA, USA
³ Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
⁴ Department of Dermatology, Southern General Hospital, Glasgow, UK
⁵ Department of Dermatology, University of Glasgow, UK

View larger version (50K): [in a new window]   Fig. 1. Palmoplantar keratoderma associated with deafness in a family carrying mutation E42 in GJB2. (A) Mild, diffuse hyperkeratosis of the sole with accentuated skin markings and marked callus formation over the pressure points (II-1 in C). (B) Transgradient, erythematous, hyperkeratotic plaques on the left foot (III-2 in C). (C) Pedigree of the three-generation family. Black symbols indicate HI; spotted symbols indicate PPK; white symbols represent unaffected individuals. Individual genotypes for both mutations, 35delG and 124delAGG, are shown below symbols. (D) Sequence chromatograms for 35delG in II-1, II-2 and III-2 (left to right). (E) Sequence chromatograms for 125delAGG in II-2, III-2 and the sub-cloned mutant allele (left to right).

View larger version (43K): [in a new window]   Fig. 2. Functional analysis of wild-type and/or mutant Cx26 co-expressed with wtCx43 or wtCx37 in Xenopus oocytes. The bars represent the junctional conductance established between two cells (mean±s.e.m.). The relative functional activity of gap junctional channels is given in percent. (A) Cx26 mutants are functionally inactive. (B) Cx26 mutants dominantly inhibit channel function of co-expressed wtCx26. (C) Cx26 mutants causing PPK/HI suppress channel activity of co-expressed wtCx43 (trans-dominant effect). (D) Cx26 mutants exert variable effects on the function of wtCx37 channels.

View larger version (101K): [in a new window]   Fig. 3. Double immunofluorescence of normal and lesional skin with Cx26 (green) and Cx43 (red) antibodies. (A) Normal plantar skin. (B) Lesional plantar skin of II-1 (carrier of E42). Areas of focal co-localization of Cx26 and Cx43 are shown in yellow. (C) Lesional skin of the lateral foot of III-2 (compound heterozygous for E42/35delG). Normal expression of Cx26 by the epithelium of an eccrine sweat duct with punctate staining of the plasma membranes. Note the focal co-localization of Cx26 and Cx43 in suprabasal keratinocytes surrounding the sweat duct. (D) Normal-appearing skin (arm) of II-2 (homozygous 35delG mutation carrier) with absent immunostaining of Cx26. (E) Normal-appearing skin (arm) of II-1 (carrier of E42) demonstrating basal expression of Cx26 with extension into the lower suprabasal cells which results occasionally in co-localization of Cx26 and Cx43. (F) Viral wart. Epidermal hyperproliferation is associated with strong expression of Cx26 throughout the upper epidermis and extensive co-localization of Cx26 and Cx43.e, epidermis; d, dermis; sd, sweat duct. Bar, 40 µm (A,B,C,F); 24 µm (D); 120 µm (E).