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From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome

2016; Elsevier BV; Volume: 136; Issue: 3 Linguagem: Inglês

10.1016/j.jid.2015.11.017

ISSN

1523-1747

Autores

Isaac E. García, Felicitas Bosen, Paula Mujica, Amaury Pupo, Carolina Flores‐Muñoz, Oscar Jara, Carlos González, Klaus Willecke, Agustı́n D. Martı́nez,

Tópico(s)

Nicotinic Acetylcholine Receptors Study

Resumo

The keratitis-ichthyosis-deafness (KID) syndrome is characterized by corneal, skin, and hearing abnormalities. KID has been linked to heterozygous dominant missense mutations in the GJB2 and GJB6 genes, encoding connexin26 and 30, respectively. In vitro evidence indicates that KID mutations lead to hyperactive (open) hemichannels, which in some cases is accompanied by abnormal function of gap junction channels. Transgenic mouse models expressing connexin26 KID mutations reproduce human phenotypes and present impaired epidermal calcium homeostasis and abnormal lipid composition of the stratum corneum affecting the water barrier. Here we have compiled relevant data regarding the KID syndrome and propose a mechanism for the epidermal aspects of the disease. The keratitis-ichthyosis-deafness (KID) syndrome is characterized by corneal, skin, and hearing abnormalities. KID has been linked to heterozygous dominant missense mutations in the GJB2 and GJB6 genes, encoding connexin26 and 30, respectively. In vitro evidence indicates that KID mutations lead to hyperactive (open) hemichannels, which in some cases is accompanied by abnormal function of gap junction channels. Transgenic mouse models expressing connexin26 KID mutations reproduce human phenotypes and present impaired epidermal calcium homeostasis and abnormal lipid composition of the stratum corneum affecting the water barrier. Here we have compiled relevant data regarding the KID syndrome and propose a mechanism for the epidermal aspects of the disease. The keratitis-ichthyosis-deafness syndrome (KID) is a genetic disorder inherited in an autosomal dominant manner, with few cases of recessive inheritance (Burns, 1915Burns F. A case of generalized congenital erythroderma.J Cutan Dis. 1915; 33: 255-260Google Scholar, Caceres-Rios et al., 1996Caceres-Rios H. Tamayo-Sanchez L. Duran-Mckinster C. de la Luz Orozco M. Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology.Pediatr Dermatol. 1996; 13: 105-113Crossref PubMed Google Scholar, Orozco-Covarrubias et al., 2008Orozco-Covarrubias L. Sáez-de-Ocariz M. Durán-McKinster C. Ruiz-Maldonado R. KID Syndrome (keratitis-ichthyosis-deafness). Neurocutaneous disorders: phakomatoses & hamartoneoplasis syndromes. Springer, Wien New York2008: p. 625Google Scholar, Skinner et al., 1981Skinner B.A. Greist M.C. Norins A.L. The keratitis, ichthyosis, and deafness (KID) syndrome.Arch Dermatol. 1981; 117: 285-289Crossref PubMed Google Scholar). Hallmarks of the KID syndrome include eye problems, skin abnormalities, and severe hearing loss. Keratitis is characterized by corneal inflammation and pain, increased light sensitivity (photophobia), corneal neovascularization, and conjunctivitis. In severe cases, patients may become blind (Orozco-Covarrubias et al., 2008Orozco-Covarrubias L. Sáez-de-Ocariz M. Durán-McKinster C. Ruiz-Maldonado R. KID Syndrome (keratitis-ichthyosis-deafness). Neurocutaneous disorders: phakomatoses & hamartoneoplasis syndromes. Springer, Wien New York2008: p. 625Google Scholar). The main skin abnormalities included thickening of soles and palms (palmoplantar keratoderma [PPK]), furfuraceous, or dry/scaling (ichthyosis) in reddish skin patches (erythrokeratoderma), which can be randomly distributed on the body but concentrated at neck and armpits (Caceres-Rios et al., 1996Caceres-Rios H. Tamayo-Sanchez L. Duran-Mckinster C. de la Luz Orozco M. Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology.Pediatr Dermatol. 1996; 13: 105-113Crossref PubMed Google Scholar). Patients also tend to develop carcinomas (Mazereeuw-Hautier et al., 2007Mazereeuw-Hautier J. Bitoun E. Chevrant-Breton J. Man S.Y. Bodemer C. Prins C. et al.Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients.Br J Dermatol. 2007; 156: 1015-1019Crossref PubMed Scopus (92) Google Scholar). This complex corneal/skin disease is accompanied by profound hearing loss (Caceres-Rios et al., 1996Caceres-Rios H. Tamayo-Sanchez L. Duran-Mckinster C. de la Luz Orozco M. Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology.Pediatr Dermatol. 1996; 13: 105-113Crossref PubMed Google Scholar, Richard et al., 2002Richard G. Rouan F. Willoughby C.E. Brown N. Chung P. Ryynanen M. et al.Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.Am J Hum Genet. 2002; 70: 1341-1348Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar). Fortunately, this severe syndrome is very rare, with approximately 100 cases reported affecting females slightly more often than males. Because the KID syndrome influences several organs, patients require multidisciplinary treatment. Unfortunately, in severe cases, the syndrome leads to death in infants because of massive skin problems and breathing disorders (Meigh et al., 2014Meigh L. Hussain N. Mulkey D.K. Dale N. Connexin26 hemichannels with a mutation that causes KID syndrome in humans lack sensitivity to CO2.Elife. 2014; 3: e04249Crossref PubMed Scopus (14) Google Scholar, Sbidian et al., 2010Sbidian E. Feldmann D. Bengoa J. Fraitag S. Abadie V. de Prost Y. et al.Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form.Clin Genet. 2010; 77: 587-592Crossref PubMed Scopus (33) Google Scholar). The application of skin-softening emollients on moist skin is helpful only in some milder cases of the KID syndrome. Although most KID syndrome cases arise from sporadic mutations, some cases of familial transmission support autosomal dominant inheritance (Grob et al., 1987Grob J.J. Breton A. Bonafe J.L. Sauvan-Ferdani M. Bonerandi J.J. Keratitis, ichthyosis, and deafness (KID) syndrome. Vertical transmission and death from multiple squamous cell carcinomas.Arch Dermatol. 1987; 123: 777-782Crossref PubMed Google Scholar, Kelly et al., 2008Kelly B. Lozano A. Altenberg G. Makishima T. Connexin 26 mutation in keratitis-ichthyosis-deafness (KID) syndrome in mother and daughter with combined conductive and sensorineural hearing loss.Int J Dermatol. 2008; 47: 443-447Crossref PubMed Scopus (0) Google Scholar, Langer et al., 1990Langer K. Konrad K. Wolff K. Keratitis, ichthyosis and deafness (KID)-syndrome: report of three cases and a review of the literature.Br J Dermatol. 1990; 122: 689-697Crossref PubMed Scopus (0) Google Scholar, Messmer et al., 2005Messmer E.M. Kenyon K.R. Rittinger O. Janecke A.R. Kampik A. Ocular manifestations of keratitis-ichthyosis-deafness (KID) syndrome.Ophthalmology. 2005; 112: e1-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Nazzaro et al., 1990Nazzaro V. Blanchet-Bardon C. Lorette G. Civatte J. Familial occurrence of KID (keratitis, ichthyosis, deafness) syndrome. Case reports of a mother and daughter.J Am Acad Dermatol. 1990; 23: 385-388Abstract Full Text PDF PubMed Google Scholar, Orozco-Covarrubias et al., 2008Orozco-Covarrubias L. Sáez-de-Ocariz M. Durán-McKinster C. Ruiz-Maldonado R. KID Syndrome (keratitis-ichthyosis-deafness). Neurocutaneous disorders: phakomatoses & hamartoneoplasis syndromes. Springer, Wien New York2008: p. 625Google Scholar). The autosomal dominant form of KID has been linked to heterozygous missense mutations in the GJB2 gene, which codes for the connexin26 protein (Cx26; GJB2 13q11-12) (Richard et al., 2002Richard G. Rouan F. Willoughby C.E. Brown N. Chung P. Ryynanen M. et al.Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.Am J Hum Genet. 2002; 70: 1341-1348Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, van Steensel et al., 2002van Steensel M.A. van Geel M. Nahuys M. Smitt J.H. Steijlen P.M. A novel connexin 26 mutation in a patient diagnosed with keratitis-ichthyosis-deafness syndrome.J Invest Dermatol. 2002; 118: 724-727Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar) and in the GJB6 gene, which encodes the connexin30 protein (Cx30; GJB6 13q12). To date 14 different missense mutations (12 in GJB2; 2 in GJB6) have been identified in patients with KID (summarized in Table 1). Recently, a lethal form of KID was described, caused by reversion of the GJB2 nonsense mutation Y136X that has confined the effect of KID mutation G45E present in the same allele (Ogawa et al., 2014Ogawa Y. Takeichi T. Kono M. Hamajima N. Yamamoto T. Sugiura K. et al.Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis.PLoS Genet. 2014; 10: e1004276Crossref PubMed Google Scholar). The authors estimated that there are approximately 11,000 individuals in the Japanese population that carry both the Cx26G45E mutation and the confining Y136X mutation. These tandem mutations can cause hearing loss in an autosomal recessive manner. Because most of these individuals are heterozygous for the tandem alleles, they do not suffer from hearing loss. The reason for the relatively frequent coexistence of both mutations is unknown, but it is possible that certain mutations may protect the apparition of a disease phenotype caused by mutations in the same or the other allele.Table 1Exogenous characterization of connexin channels from patients with KID or Clouston syndromeConnexinMutationHemichannel activityGap junction channel functionDiseaseClinical signs and symptomsCx26G11EIncreased Ca2+ uptake (Sánchez and Verselis, 2014Sánchez H.A. Verselis V.K. Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss.Front Cell Neurosci. 2014; 8: 354Crossref PubMed Scopus (0) Google Scholar, Terrinoni et al., 2010bTerrinoni A. Codispoti A. Serra V. Didona B. Bruno E. Nistico R. et al.Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation.Biochem Biophys Res Commun. 2010; 394: 909-914Crossref PubMed Scopus (0) Google Scholar)Not determinedKID syndromeDeafness, hyperkeratosis, palmoplantar keratoderma, ocular keratitis, and cicatricial alopecia (Terrinoni et al., 2010aTerrinoni A. Codispoti A. Serra V. Bruno E. Didona B. Paradisi M. et al.Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss.Biochem Biophys Res Commun. 2010; 395: 25-30Crossref PubMed Scopus (0) Google Scholar)G12RIncreased outward currents (Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Sánchez and Verselis, 2014Sánchez H.A. Verselis V.K. Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss.Front Cell Neurosci. 2014; 8: 354Crossref PubMed Scopus (0) Google Scholar). Hyperactive hemichannels determined by ATP release measurements (Donnelly et al., 2012Donnelly S. English G. de Zwart-Storm E.A. Lang S. van Steensel M.A. Martin P.E. Differential susceptibility of Cx26 mutations associated with epidermal dysplasias to peptidoglycan derived from Staphylococcus aureus and Staphylococcus epidermidis.Exp Dermatol. 2012; 21: 592-598Crossref PubMed Scopus (23) Google Scholar, García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Form hyperactive heteromeric hemichannels with Cx43, increased intracellular Ca2+ concentration and ATP release (García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar)Unfunctional GJCs determined through dye coupling and electrophysiology (García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Enhanced dye coupling determined by parachute assay (Donnelly et al., 2012Donnelly S. English G. de Zwart-Storm E.A. Lang S. van Steensel M.A. Martin P.E. Differential susceptibility of Cx26 mutations associated with epidermal dysplasias to peptidoglycan derived from Staphylococcus aureus and Staphylococcus epidermidis.Exp Dermatol. 2012; 21: 592-598Crossref PubMed Scopus (23) Google Scholar)KID syndromeDeafness (mild), cracked areas on palms and soles, severe acne vulgaris, and left eye keratitis (Neoh et al., 2009Neoh C.Y. Chen H. Ng S.K. Lane E.B. Common J.E. A rare connexin 26 mutation in a patient with a forme fruste of keratitis-ichthyosis-deafness (KID) syndrome.Int J Dermatol. 2009; 48: 1078-1081Crossref PubMed Scopus (0) Google Scholar). Follicular occlusion syndrome, and persistent oral mucosal papules (Lazic et al., 2012Lazic T. Li Q. Frank M. Uitto J. Zhou L.H. Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) connexin 26 mutation and unusual clinical findings.Pediatr Dermatol. 2012; 29: 349-357Crossref PubMed Scopus (0) Google Scholar)N14KIncreased outward currents (Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Sánchez and Verselis, 2014Sánchez H.A. Verselis V.K. Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss.Front Cell Neurosci. 2014; 8: 354Crossref PubMed Scopus (0) Google Scholar)No dye transfer determined by parachute assay (de Zwart-Storm et al., 2011de Zwart-Storm E.A. Rosa R.F. Martin P.E. Foelster-Holst R. Frank J. Bau A.E. et al.Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes.Exp Dermatol. 2011; 20: 408-412Crossref PubMed Scopus (18) Google Scholar). Functional GJC channels determined by electrophysiology (Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar)KID syndrome; Clouston syndromeDeafness, severe bilateral early-onset keratitis, eythokeratoderma, hypotrichosis, and squamus cell carcinoma (van Steensel et al., 2004van Steensel M.A. Steijlen P.M. Bladergroen R.S. Hoefsloot E.H. van Ravenswaaij-Arts C.M. van Geel M. A phenotype resembling the Clouston syndrome with deafness is associated with a novel missense GJB2 mutation.J Invest Dermatol. 2004; 123: 291-293Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Hyperkeratotic skin lesions, palmoplantar hyperkeratosis, perineal plaques, nail dystrophy, gingival and mucosal swelling and hyperemia, chronic lip fissuring/erythema/crusting, tongue or oral mucosa erosions, intermittent photophobia, and recurrent skin infections (Lazic et al., 2008Lazic T. Horii K.A. Richard G. Wasserman D.I. Antaya R.J. A report of GJB2 (N14K) connexin 26 mutation in two patients—a new subtype of KID syndrome?.Pediatr Dermatol. 2008; 25: 535-540Crossref PubMed Scopus (0) Google Scholar)N14YHyperactive heteromeric hemichannels with Cx43, increased intracellular Ca2+ concentration and ATP release (García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar)Reduced coupling determined by scrape-loading assay (Arita et al., 2006Arita K. Akiyama M. Aizawa T. Umetsu Y. Segawa I. Goto M. et al.A novel N14Y mutation in connexin26 in keratitis-ichthyosis-deafness syndrome: analyses of altered gap junctional communication and molecular structure of N terminus of mutated connexin26.Am J Pathol. 2006; 169: 416-423Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Unfunctional GJCs determined by dye coupling and electrophysiology (García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Allow calcein spreading in monolayer cells, determined by parachute assay (de Zwart-Storm et al., 2011de Zwart-Storm E.A. Rosa R.F. Martin P.E. Foelster-Holst R. Frank J. Bau A.E. et al.Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes.Exp Dermatol. 2011; 20: 408-412Crossref PubMed Scopus (18) Google Scholar)KID syndromeDeafness, erythrokeratoderma, palmoplantar hyperkeratosis, photophobia, keratitis, and alopecia (Arita et al., 2006Arita K. Akiyama M. Aizawa T. Umetsu Y. Segawa I. Goto M. et al.A novel N14Y mutation in connexin26 in keratitis-ichthyosis-deafness syndrome: analyses of altered gap junctional communication and molecular structure of N terminus of mutated connexin26.Am J Pathol. 2006; 169: 416-423Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Porokeratotic eccrine nevus (Easton et al., 2012Easton J.A. Donnelly S. Kamps M.A. Steijlen P.M. Martin P.E. Tadini G. et al.Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations.J Invest Dermatol. 2012; 132: 2184-2191Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar)S17FDoes not form functional hemichannels (García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Schütz et al., 2011Schütz M. Auth T. Gehrt A. Bosen F. Korber I. Strenzke N. et al.The connexin26 S17F mouse mutant represents a model for the human hereditary keratitis-ichthyosis-deafness syndrome.Hum Mol Genet. 2011; 20: 28-39Crossref PubMed Scopus (0) Google Scholar). Hyperactive homomeric hemichannels with wtCx26; hyperactive heteromeric hemichannels with Cx43, increased intracellular Ca2+ concentration and ATP release (García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar)No GJ coupling determined by dye transfer and electrophysiology (García et al., 2015García I.E. Maripillán J. Jara O. Ceriani R. Palacios-Muñoz A. Ramachandran J. et al.Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.J Invest Dermatol. 2015; 135: 1338-1347Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Schütz et al., 2011Schütz M. Auth T. Gehrt A. Bosen F. Korber I. Strenzke N. et al.The connexin26 S17F mouse mutant represents a model for the human hereditary keratitis-ichthyosis-deafness syndrome.Hum Mol Genet. 2011; 20: 28-39Crossref PubMed Scopus (0) Google Scholar)KID syndromeDeafness, erythrokeratoderma, palmoplantar hyperkeratosis, photophobia, keratitis, alopecia, and carcinogenic potential (Mazereeuw-Hautier et al., 2007Mazereeuw-Hautier J. Bitoun E. Chevrant-Breton J. Man S.Y. Bodemer C. Prins C. et al.Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients.Br J Dermatol. 2007; 156: 1015-1019Crossref PubMed Scopus (92) Google Scholar)A40VImpaired regulation by extracellular Ca2+ (Sánchez and Verselis, 2014Sánchez H.A. Verselis V.K. Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss.Front Cell Neurosci. 2014; 8: 354Crossref PubMed Scopus (0) Google Scholar), pH, and Zn2+ (Sánchez et al., 2010Sánchez H.A. Mese G. Srinivas M. White T.W. Verselis V.K. 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. 2010; 136: 47-62Crossref PubMed Scopus (104) Google Scholar, Sánchez et al., 2014Sánchez H.A. Bienkowski R. Slavi N. Srinivas M. Verselis V.K. Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome.J Biol Chem. 2014; 289: 21519-21532Crossref PubMed Scopus (20) Google Scholar). Increased whole cell currents. Leaky hemichannels (Gerido et al., 2007Gerido D.A. DeRosa A.M. Richard G. White T.W. Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness.Am J Physiol Cell Physiol. 2007; 293: C337-C345Crossref PubMed Scopus (0) Google Scholar, Sánchez et al., 2010Sánchez H.A. Mese G. Srinivas M. White T.W. Verselis V.K. 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. 2010; 136: 47-62Crossref PubMed Scopus (104) Google Scholar)Disrupted GJC activity determined by electrophysiology (Montgomery et al., 2004Montgomery J.R. White T.W. Martin B.L. Turner M.L. Holland S.M. A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad.J Am Acad Dermatol. 2004; 51: 377-382Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)KID syndromeDeafness, mild palmoplantar keratoderma, ichthyosiform scaling, follicular hyperkeratosis, and mild keratitis, severe inflammation and folliculitis of the scalp, hidradenitis suppurativa, and cystic acne (Montgomery et al., 2004Montgomery J.R. White T.W. Martin B.L. Turner M.L. Holland S.M. A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad.J Am Acad Dermatol. 2004; 51: 377-382Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)G45EAberrant hemichannel activity, increased voltage sensitive gating, increased Ca2+ permeability (Gerido et al., 2007Gerido D.A. DeRosa A.M. Richard G. White T.W. Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness.Am J Physiol Cell Physiol. 2007; 293: C337-C345Crossref PubMed Scopus (0) Google Scholar, Mese et al., 2011Mese G. Sellitto C. Li L. Wang H.Z. Valiunas V. Richard G. et al.The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome.Mol Biol Cell. 2011; 22: 4776-4786Crossref PubMed Scopus (55) Google Scholar, Sánchez et al., 2010Sánchez H.A. Mese G. Srinivas M. White T.W. Verselis V.K. 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. 2010; 136: 47-62Crossref PubMed Scopus (104) Google Scholar, Stong et al., 2006Stong B.C. Chang Q. Ahmad S. Lin X. A novel mechanism for connexin 26 mutation linked deafness: cell death caused by leaky gap junction hemichannels.Laryngoscope. 2006; 116: 2205-2210Crossref PubMed Scopus (90) Google Scholar)Functional GJCs determined by electrophysiology (Gerido et al., 2007Gerido D.A. DeRosa A.M. Richard G. White T.W. Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness.Am J Physiol Cell Physiol. 2007; 293: C337-C345Crossref PubMed Scopus (0) Google Scholar, Mese et al., 2011Mese G. Sellitto C. Li L. Wang H.Z. Valiunas V. Richard G. et al.The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome.Mol Biol Cell. 2011; 22: 4776-4786Crossref PubMed Scopus (55) Google Scholar, Stong et al., 2006Stong B.C. Chang Q. Ahmad S. Lin X. A novel mechanism for connexin 26 mutation linked deafness: cell death caused by leaky gap junction hemichannels.Laryngoscope. 2006; 116: 2205-2210Crossref PubMed Scopus (90) Google Scholar)KID syndromeDysplasia of the cochlear and saccular neuroepithelium. Neonatal phenotype: facial dysmorphy, severe cornification with massive focal hyperkeratosis of the skin with erythroderma, dystrophic nails, complete atrichia, and absence of foreskin (Griffith et al., 2006Griffith A.J. Yang Y. Pryor S.P. Park H.J. Jabs E.W. Nadol Jr., J.B. et al.Cochleosaccular dysplasia associated with a connexin 26 mutation in keratitis-ichthyosis-deafness syndrome.Laryngoscope. 2006; 116: 1404-1408Crossref PubMed Scopus (35) Google Scholar). Some cases of lethal breathing failures (Janecke et al., 2005Janecke A.R. Hennies H.C. Gunther B. Gansl G. Smolle J. 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Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss.Front Cell Neurosci. 2014; 8: 354Crossref PubMed Scopus (0) Google Scholar)Not determinedNot determinedDeafness (severe), keratitis, hyperkeratosis, and Dandy-Walker malformation (Cushing et al., 2008Cushing S.L. MacDonald L. Propst E.J. Sharma A. Stockley T. Blaser S.L. et al.Successful cochlear implantation in a child with keratosis, icthiosis and deafness (KID) syndrome and Dandy-Walker malformation.Int J Pediatr Otorhinolaryngol. 2008; 72: 693-698Crossref PubMed Scopus (0) Google Scholar)D50NLoss of inhibition by extracellular Ca2+, decreased unitary conductance, increased open hemichannel current rectification and voltage-shifted activation (Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Lopez et al., 2013Lopez W. Gonzalez J. Liu Y. Harris A.L. Contreras J.E. Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N/Y).J Gen Physiol. 2013; 142: 23-35Crossref PubMed Scopus (38) Google Scholar, Terrinoni et al., 2010bTerrinoni A. Codispoti A. Serra V. Didona B. Bruno E. Nistico R. et al.Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation.Biochem Biophys Res Commun. 2010; 394: 909-914Crossref PubMed Scopus (0) Google Scholar)Do not produce functional GJC currents in pairs of Xenopus oocytes (Lee et al., 2009Lee J.R. Derosa A.M. White T.W. Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in xenopus oocytes.J Invest Dermatol. 2009; 129: 870-878Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Enhanced dye coupling determined by parachute assay (Donnelly et al., 2012D

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