Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis

Abstract

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…94 Diseases relatively new in the list of ichthyoses are loricrin keratoderma, also referred to as Camisa variant of Vohwinkel keratoderma (Fig 4, C ), [95][96][97] the cerebral dysgenesiseneuropathyeichthyosisePPK syndrome, 98 the arthrogryposiserenal dysfunctionecholestasis syndrome, 99-101 the mental retardationeenteropathye deafnesseneuropathyeichthyosisekeratodermia syndrome, 102 the ichthyosisehypotrichosisesclerosing cholangitis syndrome (also known as neonatal ichthyosis sclerosing cholangitis syndrome), 103-105 the ichthyosis hypotrichosis syndrome (Fig 5, I ) 106 and its allelic variant congenital ichthyosisefollicular atrophodermaehypotrichosisehypohidrosis syndrome, 107,108 and keratosis lineariseichthyosisecongenital sclerosing keratoderma (Fig 4, F ). 109,110 Erythrokeratodermia variabilis (EKV), [111][112][113] which is characterized by migratory erythematous patches and more fixed, symmetric hyperkeratotic plaques often with palmoplantar involvement (Fig 4, B), is genetically heterogeneous and can in 50% to 65% of cases 114 be caused by mutations in GJB3 coding for the gap junction protein connexin 31, 115 or GJB4 coding for connexin 30.3. 116 Whether Acral PSS, Acral peeling skin syndrome; AD, autosomal dominant; AR, autosomal recessive; CE, cornified cell envelope; CIE, congenital ichthyosiform erythroderma; EKV, erythrokeratodermia variabilis; IE, ichthyosiform erythroderma; KG, keratohyaline granules; KLICK, keratosis lineariseichthyosis congenitaekeratoderma; LB, lamellar body; LK, loricrin keratoderma; PPK, palmoplantar keratoderma; PSD, peeling skin disease; SC, stratum corneum; SG, stratum granulosum.…”

Cx31 is assembled and trafficked to cell surface by ER-Golgi pathway and degraded by proteasomal or lysosomal pathways

“…Mutations in Cx31 would cause erythrokeratodermia variabilis (EKV), hearing impairment, and peripheral neuropathy, respectively [4][5][6][7]. However, the mechanism of Cx31 in the pathogenesis of these diseases remains unclear.…”

Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafness

“…Connexin 31 (Cx31) is one of several connexins associated with human disease (see Supporting Text, which is published as supporting information on the PNAS web site, for further details and references). Cx31 is expressed in skin (1,2), and mutations in the human gene (GJB3) are associated with the genetic skin disorder erythrokeratodermia variabilis (3,4). Cx31 is also expressed in the mouse cochlea (5,6) and in peripheral auditory nerves (7), which may explain the association of some mutations in Cx31 with deafness (8).…”

“…Similarly, studies of human Cx31 (hCx31) suggest that mutations in this connexin may also lead to alterations in trafficking or channel function (26)(27)(28), and some mutations increase cell death when expressed in HeLa, NIH 3T3, or NEB1 cells (26,29). Although mutations in the gene for hCx31 have been associated with autosomal recessive deafness (30) or skin disease (31), most pathogenic hCx31 mutations lead to dominantly inherited disease (3,4,30) and are likely to be caused by either toxic gain-of-function or dominant-negative interactions.…”