Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders

Abstract

To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm. Light and electron microscopy showed marked thickening of the epidermal cornified layers and increased epidermal TUNEL staining, indicative of premature keratinocyte programmed cell death. The K10Connexin 26(D66H) mouse may provide a valuable model to study the role of gap-junctional intercellular communication in epidermal differentiation. Similarities in phenotype between individuals (man and mouse) carrying Connexin 26(D66H) and those carrying insertional mutants of Loricrin, a major cornified envelope protein of the epidermis, suggest a possible link between connexin function and cornified envelope formation.

Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies

“…This is consistent with findings for the G59A and D66H Cx26 mutants that are linked to Vohwinkel syndrome (Bakirtzis et al, 2003;Marziano et al, 2003;Thomas et al, 2004), suggesting that mutations in the first extracellular domain of Cx30 and Cx26 might lead to similar disease phenotypes. Supporting an essential role for the first extracellular loop, the N45K Cx26 mutation located in this domain causes Bart-Pumphrey syndrome .…”

“…This patient experienced Clouston-syndrome-like symptoms but also hearing impairment and vascularising keratitis (Jan et al, 2004). Finally, a G59R mutation results in the development of classical Vohwinkel syndrome and Bart-Pumphrey syndrome (Nemoto-Hasebe et al, 2009), which are also diseases that are most commonly caused by mutations in Cx26 (Bakirtzis et al, 2003;Jan et al, 2004;Richard et al, 2004). Both syndromes result in PPK and sensorineural hearing loss, however, BartPumphrey syndrome can be distinguished by the formation of knuckle pads, whereas patients with Vohwinkel syndrome develop constriction bands that cause spontaneous autoamputation of the digits (pseudoainhum) (Bakirtzis et al, 2003;Richard et al, 2004).…”

Defective Epidermal Barrier in Neonatal Mice Lacking the C-Terminal Region of Connexin43

“…The very compact s. corneum locally invaginated and led to the observed constriction rings. A similar phenotype was documented by Bakirtzis et al (2003) in mice expressing mutant Cx26 (Cx26D66H). Recent analysis of s. corneum functions in human patients suffering from the loricrin linked form of Vohwinkel disease also attributed the abnormalities to impairments of the epidermal permeability barrier accompanied by defects in desquamation and the occurrence of corneocytic fragility (Schmuth et al, 2004).…”

“…Vohwinkel's disease has been linked to mutations in the loricrin and cx26 genes (Korge et al, 1997;van Steensel et al, 2002). Mice expressing mutated loricrin or Cx26 protein model the phenotype of this disease (Suga et al, 2000;Bakirtzis et al, 2003). In comparison with wild-type littermates, tails of homozygous Cx43K258stop neonates showed a completely smooth surface in preliminary SEM analysis with no signs of desquamation.…”

Defective channels lead to an impaired skin barrier

“…These skin-disease-associated connexin mutants appear to either suppress wild-type gap junction channel activity by exerting a dominant-negative effect on wild-type connexins or a transdominant effect on other connexin proteins (Rouan et al, 2001), or represent gain-of-function variants (Richard et al, 1998;Bakirtzis et al, 2003;Essenfelder et al, 2004;Gerido et al, 2007;Lee et al, 2009). For example, mutant forms of Cx31 can traffic incorrectly and accumulate in organelles such as the ER, causing ER stress and activation of the unfolded protein response (UPR), which results in cell death (Tattersall et al, 2009).…”