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Connexins and skin disease: insights into the role of beta connexins in skin homeostasis

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Abstract

Cell-to-cell communication triggered by connexin channels plays a central role in maintaining epidermal homeostasis. Here, we discuss the role of the beta connexin subgroup, where site-specific mutations in at least 4 of these proteins lead to distinctive non-inflammatory and inflammatory hyperproliferative epidermal disorders. Recent advances in the molecular pathways evoked and correlation with clinical outcome are discussed. The latest data provide increasing evidence that connexins in the epidermis are sensors to environmental stress and that targeting aberrant hemichannel activity holds significant therapeutic potential for inflammatory skin disorders.

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Abbreviations

Cx:

Connexin

E1/E2:

Extracellular loop domain

EKV-P:

Erythrokeratodermia variabilis et progressiva

ER:

Endoplasmic reticulum

GJ:

Gap junction

IL-6:

Interleukin-6

KID:

Keratitis ichthyosis deafness syndrome

PGN:

Peptidoglycan

PPK:

Palmoplantar keratoderma

REK:

Rat epidermal keratinocytes

ROS:

Reactive oxygen species

TM:

Transmembrane domain.

References

  • Abascal F, Zardoya R (2013) Evolutionary analyses of gap junction protein families. Biochim Biophys Acta 1828:4–14

    CAS  PubMed  Google Scholar 

  • Akiyama M, Sakai K, Arita K, Nomura Y, Ito K, Kodama K, McMillan JR, Kobayashi K, Sawamura D, Shimizu H (2007) A novel GJB2 mutation p.Asn54His in a patient with palmoplantar keratoderma, sensorineural hearing loss and knuckle pads. J Invest Dermatol 127:1540–1543

    CAS  PubMed  Google Scholar 

  • Araya-Secchi R, Perez-Acle T, Kang SG, Huynh T, Bernardin A, Escalona Y, Garate JA, Martinez AD, Garcia IE, Saez JC, Zhou R (2014) Characterization of a novel water pocket inside the human Cx26 hemichannel structure. Biophys J 107:599–612

    CAS  PubMed  Google Scholar 

  • Bakirtzis G, Choudhry R, Aasen T, Shore L, Brown K, Bryson S, Forrow S, Tetley L, Finbow M, Greenhalgh D, Hodgins M (2003a) Targeted epidermal expression of mutant Connexin 26 (D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. Hum Mol Gen 12:1737–1744

    CAS  PubMed  Google Scholar 

  • Bakirtzis G, Jamieson S, Aasen T, Bryson S, Forrow S, Tetley L, Finbow M, Greenhalgh D, Hodgins M (2003b) The effects of a mutant connexin 26 on epidermal differentiation. Cell Commun Adhes 10:359–364

    CAS  PubMed  Google Scholar 

  • Baris HN, Zlotogorski A, Peretz-Amit G, Doviner V, Shohat M, Reznik-Wolf H, Pras E (2008) A novel GJB6 missense mutation in hidrotic ectodermal dysplasia 2 (Clouston syndrome) broadens its genotypic basis. Br J Dermatol 159:1373–1376

    CAS  PubMed  Google Scholar 

  • Barr TP, Albrecht PJ, Hou Q, Mongin AA, Strichartz GR, Rice FL (2013) Air-stimulated ATP release from keratinocytes occurs through connexin hemichannels. PLoS ONE 8:e56744

    PubMed Central  CAS  PubMed  Google Scholar 

  • Becker DL, Thrasivoulou C, Phillips AR (2012) Connexins in wound healing; perspectives in diabetic patients. Biochim Biophys Acta 1818:2068–2075

    CAS  PubMed  Google Scholar 

  • Bejarano E, Yuste A, Patel B, Stout RF Jr, Spray DC, Cuervo AM (2014) Connexins modulate autophagosome biogenesis. Nat Cell Biol 16:401–414

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bennett MV, Garre JM, Orellana JA, Bukauskas FF, Nedergaard M, Saez JC (2012) Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res 1487:3–15

    PubMed Central  CAS  PubMed  Google Scholar 

  • Berger AC, Kelly JJ, Lajoie P, Shao Q, Laird DW (2014) Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies. J Cell Sci 127:1751–1764

    CAS  PubMed  Google Scholar 

  • Birkenhager R, Lublinghoff N, Prera E, Schild C, Aschendorff A, Arndt S (2010) Autosomal dominant prelingual hearing loss with palmoplantar keratoderma syndrome: Variability in clinical expression from mutations of R75W and R75Q in the GJB2 gene. Am J Med Gen 152a:1798–1802

    Google Scholar 

  • Blanpain C, Fuchs E (2009) Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 10:207–217

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bosen F, Schutz M, Beinhauer A, Strenzke N, Franz T, Willecke K (2014) The Clouston syndrome mutation connexin30 A88V leads to hyperproliferation of sebaceous glands and hearing impairments in mice. FEBS Lett 588:1795–1801

    CAS  PubMed  Google Scholar 

  • Brandner JM, Houdek P, Husing B, Kaiser C, Moll I (2004) Connexins 26, 30, and 43: differences among spontaneous, chronic, and accelerated human wound healing. J Invest Dermatol 122:1310–1320

    CAS  PubMed  Google Scholar 

  • Brown CW, Levy ML, Flaitz CM, Reid BS, Manolidis S, Hebert AA, Bender MM, Heilstedt HA, Plunkett KS, Fang P, Roa BB, Chung P, Tang HY, Richard G, Alford RL (2003) A novel GJB2 (connexin 26) mutation, F142L, in a patient with unusual mucocutaneous findings and deafness. J Invest Dermatol 121:1221–1223

    CAS  PubMed  Google Scholar 

  • Burnstock G, Knight GE, Greig AV (2012) Purinergic signaling in healthy and diseased skin. J Invest Dermatol 132:526–546

    CAS  PubMed  Google Scholar 

  • Ceelen L, Haesebrouck F, Vanhaecke T, Rogiers V, Vinken M (2011) Modulation of connexin signaling by bacterial pathogens and their toxins. Cell Mol Life Sci 68:3047–3064

    CAS  PubMed  Google Scholar 

  • Chi J, Li L, Liu M, Tan J, Tang C, Pan Q, Wang D, Zhang Z (2012) Pathogenic connexin-31 forms constitutively active hemichannels to promote necrotic cell death. PLoS ONE 7:e32531

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chin KY (2011) Connexins, a new target in wound treatment. J Wound Care 20:386–390

    CAS  PubMed  Google Scholar 

  • Clarke TC, Williams OJ, Martin PE, Evans WH (2009) ATP release by cardiac myocytes in a simulated ischaemia model: inhibition by a connexin mimetic and enhancement by an antiarrhythmic peptide. Eur J Pharmacol 605:9–14

    CAS  PubMed  Google Scholar 

  • Coggshall K, Farsani T, Ruben B, McCalmont TH, Berger TG, Fox LP, Shinkai K (2013) Keratitis, ichthyosis, and deafness syndrome: a review of infectious and neoplastic complications. J Am Acad Dermatol 69:127–134

    PubMed  Google Scholar 

  • Common JE, Di WL, Davies D, Kelsell DP (2004) Further evidence for heterozygote advantage of GJB2 deafness mutations: a link with cell survival. J Med Genet 41:573–575

    PubMed Central  CAS  PubMed  Google Scholar 

  • Danesh-Meyer HV, Kerr NM, Zhang J, Eady EK, O'Carroll SJ, Nicholson LF, Johnson CS, Green CR (2012) Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia. Brain 135:506–520

    PubMed  Google Scholar 

  • Davidson JO, Green CR, Nicholson LF, O’Carroll SJ, Fraser M, Bennet L, Gunn AJ (2012) Connexin hemichannel blockade improves outcomes in a model of fetal ischemia. Ann Neurol 71:121–132

    CAS  PubMed  Google Scholar 

  • Davis NG, Phillips A, Becker DL (2013) Connexin dynamics in the privileged wound healing of the buccal mucosa. Wound Rep Regen 21:571–578

    Google Scholar 

  • de Andrade AC, Vieira DC, Harris OM, Pithon MM (2014) Clouston syndrome associated with eccrine syringofibroadenoma. An Bras Dermatol 89:504–506

    PubMed Central  PubMed  Google Scholar 

  • De Vuyst E, Decrock E, De Bock M, Yamasaki H, Naus CC, Evans WH, Leybaert L (2007) Connexin hemichannels and gap junction channels are differentially influenced by lipopolysaccharide and basic fibroblast growth factor. Mol Biol Cell 18:34–46

    PubMed Central  PubMed  Google Scholar 

  • de Zwart-Storm EA, Hamm H, Stoevesandt J, Steijlen PM, Martin PE, van Geel M, van Steensel MA (2008a) A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness. J Med Genet 45:161–166

    PubMed  Google Scholar 

  • de Zwart-Storm EA, van Geel M, van Neer PA, Steijlen PM, Martin PE, van Steensel MA (2008b) A novel missense mutation in the second extracellular domain of GJB2, p.Ser183Phe, causes a syndrome of focal palmoplantar keratoderma with deafness. Am J Pathol 173:1113–1119

    PubMed Central  PubMed  Google Scholar 

  • de Zwart-Storm EA, Martin PE, van Steensel MAM (2009) Gap junction diseases of the skin – novel insights from new mutations. Expert Rev Dermatol 4:455–468

    Google Scholar 

  • de Zwart-Storm EA, Rosa RF, Martin PE, Foelster-Holst R, Frank J, Bau AE, Zen PR, Graziadio C, Paskulin GA, Kamps MA, van Geel M, van Steensel MA (2011a) Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes. Exp Dermatol 20:408–412

    PubMed  Google Scholar 

  • de Zwart-Storm EA, van Geel M, Veysey E, Burge S, Cooper S, Steijlen PM, Martin PE, van Steensel MA (2011b) A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. Br J Dermatol 164:197–199

    PubMed  Google Scholar 

  • del Castillo FJ, Cohen-Salmon M, Charollais A, Caille D, Lampe PD, Chavrier P, Meda P, Petit C (2010) Consortin, a trans-Golgi network cargo receptor for the plasma membrane targeting and recycling of connexins. Hum Mol Genet 19:262–275

    PubMed Central  PubMed  Google Scholar 

  • Di WL, Rugg EL, Leigh IM, Kelsell DP (2001) Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31. J Invest Dermatol 117:958–964

    CAS  PubMed  Google Scholar 

  • Djalilian AR, McGaughey D, Patel S, Seo EY, Yang C, Cheng J, Tomic M, Sinha S, Ishida-Yamamoto A, Segre JA (2006) Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response. J Clin Invest 116:1243–1253

    PubMed Central  CAS  PubMed  Google Scholar 

  • Djalilian AR, Kim JY, Saeed HN, Holland EJ, Chan CC (2011) Histopathology and treatment of corneal disease in keratitis, ichthyosis, and deafness (KID) syndrome. Eye (Lond) 24:738–740

    Google Scholar 

  • Donnelly S, English G, de Zwart-Storm EA, Lang S, van Steensel MA, Martin PE (2012) Differential susceptibility of Cx26 mutations associated with epidermal dysplasias to peptidoglycan derived from Staphylococcus aureus and Staphylococcus epidermidis. Exp Dermatol 21:592–598

    CAS  PubMed  Google Scholar 

  • Dunn CA, Lampe PD (2014) Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size. J Cell Sci 127:455–464

    PubMed Central  CAS  PubMed  Google Scholar 

  • Easton JA, Petersen JS, Martin PE (2009) The anti-arrhythmic peptide AAP10 remodels Cx43 and Cx40 expression and function. Naunyn Schmiedebergs Arch Pharmacol 380:11–24

    CAS  PubMed  Google Scholar 

  • Easton JA, Donnelly S, Kamps MA, Steijlen PM, Martin PE, Tadini G, Janssens R, Happle R, van Geel M, van Steensel MA (2012) Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations. J Invest Dermatol 132:2184–2191

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ek-Vitorin JF, Burt JM (2013) Structural basis for the selective permeability of channels made of communicating junction proteins. Biochim Biophys Acta 1828:51–68

    PubMed Central  CAS  PubMed  Google Scholar 

  • Evans WH, Martin PE (2002) Gap junctions: structure and function (Review). Mol Membr Biol 19:121–136

    CAS  PubMed  Google Scholar 

  • Evans WH, De Vuyst E, Leybaert L (2006) The gap junction cellular internet: connexin hemichannels enter the signalling limelight. Biochem J 397:1–14

    PubMed Central  CAS  PubMed  Google Scholar 

  • Evans WH, Bultynck G, Leybaert L (2012) Manipulating connexin communication channels: use of peptidomimetics and the translational outputs. J Membr Biol 245:437–449

    PubMed Central  CAS  PubMed  Google Scholar 

  • Figueroa VA, Retamal MA, Cea LA, Salas JD, Vargas AA, Verdugo CA, Jara O, Martinez AD, Saez JC (2014) Extracellular gentamicin reduces the activity of connexin hemichannels and interferes with purinergic Ca (2+) signaling in HeLa cells. Front Cell Neurosci 8:265

    PubMed Central  PubMed  Google Scholar 

  • Fong JT, Kells RM, Gumpert AM, Marzillier JY, Davidson MW, Falk MM (2012) Internalized gap junctions are degraded by autophagy. Autophagy 8:794–811

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fuchs-Telem D, Pessach Y, Mevorah B, Shirazi I, Sarig O, Sprecher E (2011) Erythrokeratoderma variabilis caused by a recessive mutation in GJB3. Clin Exp Dermatol 36:406–411

    CAS  PubMed  Google Scholar 

  • Fujimoto A, Kurban M, Nakamura M, Farooq M, Fujikawa H, Kibbi AG, Ito M, Dahdah M, Matta M, Diab H, Shimomura Y (2013) GJB6, of which mutations underlie Clouston syndrome, is a potential direct target gene of p63. J Dermatol Sci 69:159–166

    CAS  PubMed  Google Scholar 

  • Gallo RL, Nakatsuji T (2011) Microbial symbiosis with the innate immune defense system of the skin. J Invest Dermatol 131:1974–1980

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gerido DA, DeRosa AM, Richard G, White TW (2007) Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness. Am J Physiol Cell Physiol 293:C337–345

    CAS  PubMed  Google Scholar 

  • Ghatnekar GS, O’Quinn MP, Jourdan LJ, Gurjarpadhye AA, Draughn RL, Gourdie RG (2009) Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regen Med 4:205–223

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ghatnekar G, Grek C, Armstrong DG, Desai SC, Gourdie R (2014) The Effect of a Connexin43-based peptide on the Healing of Chronic Venous Leg Ulcers: A Multicenter Randomized Trial. J Invest Dermatol. doi:10.1038/jid.2014.318

    PubMed Central  PubMed  Google Scholar 

  • Glatz M, van Steensel MA, van Geel M, Steijlen PM, Wolf P (2011) An unusual missense mutation in the GJB3 gene resulting in severe erythrokeratodermia variabilis. Acta Dermatovenereol 91:714–715

    Google Scholar 

  • Gottfried I, Landau M, Glaser F, Di WL, Ophir J, Mevorah B, Ben-Tal N, Kelsell DP, Avraham KB (2002) A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein. Hum Mol Genet 11:1311–1316

    CAS  PubMed  Google Scholar 

  • Grek CL, Rhett JM, Ghatnekar GS (2014) Cardiac to cancer: connecting connexins to clinical opportunity. FEBS Lett 588:1349–1364

    PubMed Central  CAS  PubMed  Google Scholar 

  • Haruna K, Suga Y, Oizumi A, Mizuno Y, Endo H, Shimizu T, Hasegawa T, Ikeda S (2010) Severe form of keratitis-ichthyosis-deafness (KID) syndrome associated with septic complications. J Dermatol 37:680–682

    CAS  PubMed  Google Scholar 

  • He LQ, Liu Y, Cai F, Tan ZP, Pan Q, Liang DS, Long ZG, Wu LQ, Huang LQ, Dai HP, Xia K, Xia JH, Zhang ZH (2005) Intracellular distribution, assembly and effect of disease-associated connexin 31 mutants in HeLa cells. Acta Biochim Biophys 37:547–554

    CAS  Google Scholar 

  • Janecke AR, Hennies HC, Gunther B, Gansl G, Smolle J, Messmer EM, Utermann G, Rittinger O (2005) GJB2 mutations in keratitis-ichthyosis-deafness syndrome including its fatal form. Am J Med Genet 133A:128–131

    PubMed  Google Scholar 

  • Jonard L, Feldmann D, Parsy C, Freitag S, Sinico M, Koval C, Grati M, Couderc R, Denoyelle F, Bodemer C, Marlin S, Hadj-Rabia S (2008) A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E. Eur J Med Genet 51:35–43

    PubMed  Google Scholar 

  • Kelly SM, Vanslyke JK, Musil LS (2007) Regulation of ubiquitin-proteasome system mediated degradation by cytosolic stress. Mol Biol Cell 18:4279–4291

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kniggendorf AK, Meinhardt-Wollweber M, Yuan X, Roth B, Seifert A, Fertig N, Zeilinger C (2014) Temperature-sensitive gating of hCx26: high-resolution Raman spectroscopy sheds light on conformational changes. Biomed Optics Express 5:2054–2065

    Google Scholar 

  • Labarthe MP, Bosco D, Saurat JH, Meda P, Salomon D (1998) Upregulation of connexin 26 between keratinocytes of psoriatic lesions. J Invest Dermatol 111:72–76

    CAS  PubMed  Google Scholar 

  • Laird DW (2006) Life cycle of connexins in health and disease. Biochem J 394:527–543

    PubMed Central  CAS  PubMed  Google Scholar 

  • Laird DW (2014) Syndromic and non-syndromic disease-linked Cx43 mutations. FEBS Lett 588:1339–48

    CAS  PubMed  Google Scholar 

  • Landau M, Cohen-Bar-Dayan M, Hohl D, Ophir J, Wolf CR, Gat A, Mevorah B (2002) Erythrokeratodermia variabilis with erythema gyratum repens-like lesions. Pediatr Dermatol 19:285–292

    PubMed  Google Scholar 

  • Lazic T, Horii KA, Richard G, Wasserman DI, Antaya RJ (2008) A report of GJB2 (N14K) Connexin 26 mutation in two patients–a new subtype of KID syndrome? Pediatr Dermatol 25:535–540

    PubMed  Google Scholar 

  • Lazic T, Li Q, Frank M, Uitto J, Zhou LH (2012) Extending the phenotypic spectrum of keratitisichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) Connexin 26 mutation and unusual clinical findings. Pediatr Dermatol 29:349–357

    PubMed  Google Scholar 

  • Leonard NJ, Krol AL, Bleoo S, Somerville MJ (2005) Sensorineural hearing loss, striate palmoplantar hyperkeratosis, and knuckle pads in a patient with a novel connexin 26 (GJB2) mutation. J Med Genet 42:e2

    PubMed Central  CAS  PubMed  Google Scholar 

  • Levit NA, Mese G, Basaly MG, White TW (2011) Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome. Biochim Biophys Acta 1818:2014–9

    PubMed Central  PubMed  Google Scholar 

  • Levit NA, Sellitto C, Wang HZ, Li L, Srinivas M, Brink PR, White TW (2014) Aberrant Connexin26 Hemichannels Underlying Keratitis-Ichthyosis-Deafness Syndrome are Potently Inhibited by Mefloquine. J Invest Dermatol. doi:10.1038/jid.2014.408

    PubMed  Google Scholar 

  • Li B, Tsoi LC, Swindell WR, Gudjonsson JE, Tejasvi T, Johnston A, Ding J, Stuart PE, Xing X, Kochkodan JJ, Voorhees JJ, Kang HM, Nair RP, Abecasis GR, Elder JT (2014) Transcriptome analysis of psoriasis in a large case–control sample: RNA-seq provides insights into disease mechanisms. J Invest Dermatol 134:1828–1838

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lucke T, Choudhry R, Thom R, Selmer IS, Burden AD, Hodgins MB (1999) Upregulation of connexin 26 is a feature of keratinocyte differentiation in hyperproliferative epidermis, vaginal epithelium, and buccal epithelium. J Invest Dermatol 112:354–361

    CAS  PubMed  Google Scholar 

  • Macdonald AI, Sun P, Hernandez-Lopez H, Aasen T, Hodgins MB, Edward M, Roberts S, Massimi P, Thomas M, Banks L, Graham SV (2012) A functional interaction between the MAGUK protein hDlg and the gap junction protein Connexin 43 in cervical tumour cells. Biochem J 446:9–21

    CAS  PubMed  Google Scholar 

  • Maeda S, Nakagawa S, Suga M, Yamashita E, Oshima A, Fujiyoshi Y, Tsukihara T (2009) Structure of the connexin 26 gap junction channel at 3.5 A resolution. Nature 458:597–602

    CAS  PubMed  Google Scholar 

  • Maestrini E, Korge BP, Ocana-Sierra J, Calzolari E, Cambiaghi S, Scudder PM, Hovnanian A, Monaco AP, Munro CS (1999) A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) in three unrelated families. Hum Mol Genet 8:1237–1243

    CAS  PubMed  Google Scholar 

  • Man YK, Trolove C, Tattersall D, Thomas AC, Papakonstantinopoulou A, Patel D, Scott C, Chong J, Jagger DJ, O’Toole EA, Navsaria H, Curtis MA, Kelsell DP (2007) A deafness-associated mutant human connexin 26 improves the epithelial barrier in vitro. J Membr Biol 218:29–37

    PubMed Central  CAS  PubMed  Google Scholar 

  • Martin PE, Blundell G, Ahmad S, Errington RJ, Evans WH (2001) Multiple pathways in the trafficking and assembly of connexin 26, 32 and 43 into gap junction intercellular communication channels. J Cell Sci 114:3845–3855

    CAS  PubMed  Google Scholar 

  • Martin PE, Easton JA, Hodgins MB, Wright CS (2014) Connexins: sensors of epidermal integrity that are therapeutic targets. FEBS Lett 588:1304–1314

    CAS  PubMed  Google Scholar 

  • Mayama H, Fujimura T, Asano M, Kambayashi Y, Numata Y, Aiba S (2013) Squamous cell carcinoma arising from Keratitis-ichthyosis-deafness syndrome. Acta Derm Venereol 93:583–584

    PubMed  Google Scholar 

  • Mazereeuw-Hautier J, Bitoun E, Chevrant-Breton J, Man SY, Bodemer C, Prins C, Antille C, Saurat JH, Atherton D, Harper JI, Kelsell DP, Hovnanian A (2007) Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients. Br J Dermatol 156:1015–1019

    CAS  PubMed  Google Scholar 

  • Meigh L, Greenhalgh SA, Rodgers TL, Cann MJ, Roper DI, Dale N (2013) CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits. eLife 2:e01213

    PubMed Central  PubMed  Google Scholar 

  • Mendoza-Naranjo A, Cormie P, Serrano AE, Hu R, O’Neill S, Wang CM, Thrasivoulou C, Power KT, White A, Serena T, Phillips AR, Becker DL (2012a) Targeting Cx43 and N-cadherin, which are abnormally upregulated in venous leg ulcers, influences migration, adhesion and activation of Rho GTPases. PLoS ONE 7:e37374

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mendoza-Naranjo A, Cormie P, Serrano AE, Wang CM, Thrasivoulou C, Sutcliffe JE, Gilmartin DJ, Tsui J, Serena TE, Phillips AR, Becker DL (2012b) Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration. Cell Biol Internat 36:661–667

    CAS  Google Scholar 

  • Mese G, Sellitto C, Li L, Wang HZ, Valiunas V, Richard G, Brink PR, White TW (2011) The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome. Mol Biol Cell 22:4776–4786

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mhaske PV, Levit NA, Li L, Wang HZ, Lee JR, Shuja Z, Brink PR, White TW (2013) The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. Am J Physiol Cell Physiol 304:C1150–1158

    PubMed Central  CAS  PubMed  Google Scholar 

  • Moore K, Bryant ZJ, Ghatnekar G, Singh UP, Gourdie RG, Potts JD (2013) A synthetic connexin 43 mimetic peptide augments corneal wound healing. Exp Eye Res 115:178–88

    CAS  PubMed  Google Scholar 

  • Moore K, Ghatnekar G, Gourdie RG, Potts JD (2014) Impact of the controlled release of a connexin 43 peptide on corneal wound closure in an STZ model of type I diabetes. PLoS ONE 9:e86570

    PubMed Central  PubMed  Google Scholar 

  • Mori R, Power KT, Wang CM, Martin P, Becker DL (2006) Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J Cell Sci 119:5193–5203

    CAS  PubMed  Google Scholar 

  • Penuela S, Gehi R, Laird DW (2013) The biochemistry and function of pannexin channels. Biochim Biophys Acta 1828:15–22

    CAS  PubMed  Google Scholar 

  • Plantard L, Huber M, Macari F, Meda P, Hohl D (2003) Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. Hum Mol Genet 12:3287–3294

    CAS  PubMed  Google Scholar 

  • Ponsaerts R, D’Hondt C, Hertens F, Parys JB, Leybaert L, Vereecke J, Himpens B, Bultynck G (2012) RhoA GTPase switch controls Cx43-hemichannel activity through the contractile system. PLoS ONE 7:e42074

    PubMed Central  CAS  PubMed  Google Scholar 

  • Prasad SC, Bygum A (2013) Successful treatment with alitretinoin of dissecting cellulitis of the scalp in keratitis-ichthyosis-deafness syndrome. Acta Derm Venereol 93:473–474

    PubMed  Google Scholar 

  • Proksch E, Brandner JM, Jensen JM (2008) The skin: an indispensable barrier. Exp Dermatol 17:1063–1072

    PubMed  Google Scholar 

  • Qu C, Gardner P, Schrijver I (2009) The role of the cytoskeleton in the formation of gap junctions by Connexin 30. Exp Cell Res 315:1683–1692

    CAS  PubMed  Google Scholar 

  • Renner R, Paasch U, Simon JC, Froster UG, Heinritz W (2008) A new mutation in the GJB3 gene in a patient with erythrokeratodermia variabilis. J Eur Acad Dermatol Venerol 22:750–751

    CAS  Google Scholar 

  • Rhett JM, Jourdan J, Gourdie RG (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol Biol Cell 22:1516–1528

    PubMed Central  CAS  PubMed  Google Scholar 

  • Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH Jr, DiGiovanna JJ, Compton JG, Bale SJ (1998) Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 20:366–369

    CAS  PubMed  Google Scholar 

  • Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynanen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L (2002) Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet 70:1341–1348

    PubMed Central  CAS  PubMed  Google Scholar 

  • Richard G, Brown N, Ishida-Yamamoto A, Krol A (2004) Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2. J Invest Dermatol 123:856–863

    CAS  PubMed  Google Scholar 

  • Richardson SK, Gelfand JM (2008) Update on the natural history and systemic treatment of psoriasis. Adv Dermatol 24:171–196

    PubMed Central  PubMed  Google Scholar 

  • Robertson J, Lang S, Lambert PA, Martin PE (2010) Peptidoglycan derived from Staphylococcus epidermidis induces Connexin43 hemichannel activity with consequences on the innate immune response in endothelial cells. Biochem J 432:133–143

    CAS  PubMed  Google Scholar 

  • Sakabe J, Yoshiki R, Sugita K, Haruyama S, Sawada Y, Kabashima R, Bito T, Nakamura M, Tokura Y (2012) Connexin 26 (GJB2) mutations in keratitis-ichthyosis-deafness syndrome presenting with squamous cell carcinoma. J Dermatol 39:814–815

    CAS  PubMed  Google Scholar 

  • Sanchez HA, Mese G, Srinivas M, White TW, Verselis VK (2010) Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome. J Gen Physiol 136:47–62

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sanchez HA, Villone K, Srinivas M, Verselis VK (2013) The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions. J Gen Physiol 142:3–22

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sanchez HA, Bienkowski R, Slavi N, Srinivas M, Verselis VK (2014) Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosisdeafness syndrome. J Biol Chem 289:21519–21532

    PubMed  Google Scholar 

  • Sbidian E, Feldmann D, Bengoa J, Fraitag S, Abadie V, de Prost Y, Bodemer C, Hadj-Rabia S (2010) Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form. Clin Genet 77:587–592

    CAS  PubMed  Google Scholar 

  • Schnichels M, Worsdorfer P, Dobrowolski R, Markopoulos C, Kretz M, Schwarz G, Winterhager E, Willecke K (2007) The connexin31 F137L mutant mouse as a model for the human skin disease erythrokeratodermia variabilis (EKV). Hum Mol Genet 16:1216–1224

    CAS  PubMed  Google Scholar 

  • Schutz M, Auth T, Gehrt A, Bosen F, Korber I, Strenzke N, Moser T, Willecke K (2011) The connexin26 S17F mouse mutant represents a model for the human hereditary keratitisichthyosis-deafness syndrome. Hum Mol Genet 20:28–39

    PubMed  Google Scholar 

  • Scott CA, O’Toole EA, Mohungoo MJ, Messenger A, Kelsell DP (2011) Novel and recurrent connexin 30.3 and connexin 31 mutations associated with erythrokeratoderma variabilis. Clin Exp Dermatol 36:88–90

    CAS  PubMed  Google Scholar 

  • Seirafi H, Khezri S, Morowati S, Kamyabhesari K, Mirzaeipour M, Khezri F (2011) A new variant of Vohwinkel syndrome: a case report. Dermatol Online J 17:3

    PubMed  Google Scholar 

  • Serrano Castro PJ, Naranjo Fernandez C, Quiroga Subirana P, Payan Ortiz M (2010) Vohwinkel Syndrome secondary to missense mutation D66H in GJB2 gene (connexin 26) can include epileptic manifestations. Seizure 19:129–131

    PubMed  Google Scholar 

  • Simpson C, Kelsell DP, Marches O (2013) Connexin 26 facilitates gastrointestinal bacterial infection in vitro. Cell Tiss Res 351:107–116

    CAS  Google Scholar 

  • Smith FJ, Morley SM, McLean WH (2002) A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol 118:530–532

    CAS  PubMed  Google Scholar 

  • Snoeckx RL, Hassan DM, Kamal NM, Van Den Bogaert K, Van Camp G (2005) Mutation analysis of the GJB2 (connexin 26) gene in Egypt. Hum Mut 26:60–61

    PubMed  Google Scholar 

  • Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419:261–272

    PubMed Central  CAS  PubMed  Google Scholar 

  • Solan JL, Lampe PD (2014) Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS Lett 588:1423–1429

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sonoda S, Uchino E, Sonoda KH, Yotsumoto S, Uchio E, Isashiki Y, Sakamoto T (2004) Two patients with severe corneal disease in KID syndrome. Am J Ophthamol 137:181–183

    Google Scholar 

  • Steffens M, Gopel F, Ngezahayo A, Zeilinger C, Ernst A, Kolb HA (2008) Regulation of connexons composed of human connexin26 (hCx26) by temperature. Biochim Biophys Acta 1778:1206–1212

    CAS  PubMed  Google Scholar 

  • Su V, Lau AF (2014) Connexins: mechanisms regulating protein levels and intercellular communication. FEBS Lett 588:1212–1220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Su V, Hoang C, Geerts D, Lau AF (2014) CIP75 (connexin43-interacting protein of 75 kDa) mediates the endoplasmic reticulum dislocation of connexin43. Biochem J 458:57–67

    CAS  PubMed  Google Scholar 

  • Sun LD, Cheng H, Wang ZX, Zhang AP, Wang PG, Xu JH, Zhu QX, Zhou HS, Ellinghaus E, Zhang FR, Pu XM, Yang XQ, Zhang JZ, Xu AE, Wu RN, Xu LM, Peng L, Helms CA, Ren YQ, Zhang C, Zhang SM, Nair RP, Wang HY, Lin GS, Stuart PE, Fan X, Chen G, Tejasvi T, Li P, Zhu J, Li ZM, Ge HM, Weichenthal M, Ye WZ, Shen SK, Yang BQ, Sun YY, Li SS, Lin Y, Jiang JH, Li CT, Chen RX, Cheng J, Jiang X, Zhang P, Song WM, Tang J, Zhang HQ, Sun L, Cui J, Zhang LJ, Tang B, Huang F, Qin Q, Pei XP, Zhou AM, Shao LM, Liu JL, Zhang FY, Du WD, Franke A, Bowcock AM, Elder JT, Liu JJ, Yang S, Zhang XJ (2010) Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat Genet 42:1005–1009

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tattersall D, Scott CA, Gray C, Zicha D, Kelsell DP (2009) EKV mutant connexin 31 associated cell death is mediated by ER stress. Hum Mol Genet 18:4734–4745

    PubMed Central  CAS  PubMed  Google Scholar 

  • Terrinoni A, Codispoti A, Serra V, Bruno E, Didona B, Paradisi M, Nistico S, Campione E, Napolitano B, Diluvio L, Melino G (2010a) Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss. Biochem Biophys Res Commun 395:25–30

    CAS  PubMed  Google Scholar 

  • Terrinoni A, Codispoti A, Serra V, Didona B, Bruno E, Nistico R, Giustizieri M, Alessandrini M, Campione E, Melino G (2010b) Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation. Biochem Biophys Res Commun 394:909–914

    CAS  PubMed  Google Scholar 

  • Thomas T, Aasen T, Hodgins M, Laird DW (2003) Transport and function of cx26 mutants involved in skin and deafness disorders. Cell Commun Adhes 10:353–358

    CAS  PubMed  Google Scholar 

  • Titeux M, Mendonca V, Decha A, Moreira E, Magina S, Maia A, Lacaze-Buzy L, Mejia JE, Torrao L, Carvalho F, Eca-Guimaraes J, Hovnanian A (2009) Keratitis-ichthyosis-deafness syndrome caused by GJB2 maternal mosaicism. J Invest Dermatol 129:776–779

    CAS  PubMed  Google Scholar 

  • Torres T, Velho G, Sanches M, Selores M (2012) A case of erythrokeratodermia variabilis with connexin 31 gene mutation (Cx31F137L). Int J Dermatol 51:494–496

    CAS  PubMed  Google Scholar 

  • Tschachler E (2007) Psoriasis: the epidermal component. Clin Dermatol 25:589–595

    PubMed  Google Scholar 

  • Uyguner O, Tukel T, Baykal C, Eris H, Emiroglu M, Hafiz G, Ghanbari A, Baserer N, Yuksel-Apak M, Wollnik B (2002) The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family. Clin Genet 62:306–309

    CAS  PubMed  Google Scholar 

  • van Steensel MA, van Geel M, Nahuys M, Smitt JH, Steijlen PM (2002) A novel connexin 26 mutation in a patient diagnosed with keratitis-ichthyosis-deafness syndrome. J Invest Dermatol 118:724–727

    PubMed  Google Scholar 

  • van Steensel MA, Jonkman MF, van Geel M, Steijlen PM, McLean WH, Smith FJ (2003) Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol 121:1035–1038

    PubMed  Google Scholar 

  • van Steensel MA, Steijlen PM, Bladergroen RS, Hoefsloot EH, van Ravenswaaij-Arts CM, van Geel M (2004) A phenotype resembling the Clouston syndrome with deafness is associated with a novel missense GJB2 mutation. J Invest Dermatol 123:291–293

    PubMed  Google Scholar 

  • Van Steensel MA, Van Geel M, Steijlen PM (2005) Further delineation of the hypotrichosisdeafness syndrome. Eur J Dermatol 15:437–438

    PubMed  Google Scholar 

  • van Steensel MA, Oranje AP, van der Schroeff JG, Wagner A, van Geel M (2009) The missense mutation G12D in connexin30.3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron. Am J Med Genet 149A:657–661

    PubMed  Google Scholar 

  • Vuckovic D, Dallapiccola B, Franze A, Mauri L, Perrone MD, Gasparini P (2014) Connexin 26 variant carriers have a better gastrointestinal health: is this the heterozygote advantage? Eur J Hum Genet. doi:10.1038/ejhg.2014.151

    PubMed  Google Scholar 

  • Wang CM, Lincoln J, Cook JE, Becker DL (2007) Abnormal connexin expression underlies delayed wound healing in diabetic skin. Diabetes 56:2809–2817

    CAS  PubMed  Google Scholar 

  • Weber PA, Chang HC, Spaeth KE, Nitsche JM, Nicholson BJ (2004) The permeability of gap junction channels to probes of different size is dependent on connexin composition and permeant-pore affinities. Biophys J 87:958–973

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wright CS, van Steensel MA, Hodgins MB, Martin PE (2009) Connexin mimetic peptides improve cell migration rates of human epidermal keratinocytes and dermal fibroblasts in vitro. Wound Repair Regen 17:240–249

    PubMed  Google Scholar 

  • Wright CS, Pollok S, Flint DJ, Brandner JM, Martin PE (2012) The connexin mimetic peptide Gap27 increases human dermal fibroblast migration in hyperglycemic and hyperinsulinemic conditions in vitro. J Cell Physiol 227:77–87

    CAS  PubMed  Google Scholar 

  • Yuksek J, Sezer E, Koseoglu D, Markoc F, Yildiz H (2011) Erythrokeratodermia variabilis: successful treatment with retinoid plus psoralen and ultraviolet A therapy. J Dermatol 38:725–727

    PubMed  Google Scholar 

  • Zhang L, Hong Y, Zheng S, Huo W, Qi R, Geng L, Chen HD, Gao XH (2014) Both low-dose arotinoid ethylester and acitretin are effective in the treatment of familial erythrokeratodermia variabilis. Dermatol Ther 27:240–243

    PubMed  Google Scholar 

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Acknowledgments

In particular, we would like to thank Drs Eugene de Zwart-Storm and Steven Donnelly (S.D.) for their considerable input to these studies. Work leading to this was supported by GROW, GENE SKIN and Tenovus Scotland (S09/5) and a GCU studentship to S.D. We apologise to any colleagues whose work we have omitted to discuss in this review.

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The authors state no conflict of interest

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Authors and Affiliations

  1. Institute for Applied Health Research and Department of Life Sciences, Glasgow Caledonian University, Glasgow, G4 OBA, Scotland, UK

    Patricia E. M. Martin

  2. Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands

    Maurice van Steensel

  3. Institute of Medical Biology, Immunos, Singapore

    Maurice van Steensel

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  1. Patricia E. M. Martin
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  2. Maurice van Steensel
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Correspondence to Patricia E. M. Martin.

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Martin, P.E.M., van Steensel, M. Connexins and skin disease: insights into the role of beta connexins in skin homeostasis. Cell Tissue Res 360, 645–658 (2015). https://doi.org/10.1007/s00441-014-2094-3

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