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Heteromeric connexin (Cx)32/Cx26) (transports cAMP, cGMP and all inositol phosphates with 1-4 esterified phosphate groups (homomeric Cx26(β2) or homomeric Cx32 do not transport the inositol phosphates as well) (Ayad et al., 2006). The GJB2 gene encodes connexin 26, the protein involved in cell-cell attachment in many tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss as well as various skin disease phenotypes (Iossa et al., 2011). TMS1 regulates oligomerization and function (Jara et al., 2012).  The carboxyl tail pg Cx32 regulates gap junction assembly (Katoch et al. 2015).  In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016).  Syndromic deafness mutations at Asn14 alter the open stability of Cx26 hemichannels (Sanchez et al. 2016). The Leu89Pro substitution in the second TMS of CX32 disrupts the trafficking of the protein, inhibiting the assembly of CX32 gap junctions, which in turn may result in peripheral neuropathy (Da et al. 2016).  Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes lead to skin diseases and hearing loss, whereas mutants having reduced channel function without aberrant effects on coexpressed connexins cause only hearing loss (Press et al. 2017). When challenged by a field of 0.06 V/nm, the Cx26 hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second TMS at the level of the conserved Pro87. A point mutation that inhibited such a transition impeded hemichannel opening in electrophysiology and dye uptake experiments.  Thus, the Cx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among all connexins (Zonta et al. 2018). A group of human mutations within the N-terminal (NT) domain of connexin 26 hemichannels produce aberrant channel activity, which gives rise to deafness and skin disorders, including keratitis-ichthyosis-deafness (KID) syndrome. Structural and functional studies indicate that the NT domain of connexin hemichannels is folded into the pore, where it plays important roles in permeability and gating. The mutation, N14K disrupts cytosolic intersubunit interactions and promotes channel opening (Valdez Capuccino et al. 2018). A missense mutation in the Connexin 26 gene is associated with autosomal recessive sensorineural deafness (Leshinsky-Silver et al. 2005).

Accession Number:P29033
Protein Name:Cx26 aka Gap junction beta-2 protein
Molecular Weight:26215.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate cAMP, cGMP, Inositol phosphates, small molecules

Cross database links:

Genevestigator: P29033
eggNOG: prNOG16027
RefSeq: NP_003995.2   
Entrez Gene ID: 2706   
Pfam: PF00029    PF10582   
OMIM: 121011  gene
124500  phenotype
148210  phenotype
148350  phenotype
149200  phenotype
220290  phenotype
601544  phenotype
602540  phenotype
KEGG: hsa:2706   

Gene Ontology

GO:0005922 C:connexon complex
GO:0005793 C:ER-Golgi intermediate compartment
GO:0000139 C:Golgi membrane
GO:0016021 C:integral to membrane
GO:0007267 P:cell-cell signaling
GO:0007605 P:sensory perception of sound
GO:0006810 P:transport

References (44)

[1] “Transcriptional downregulation of gap-junction proteins blocks junctional communication in human mammary tumor cell lines.”  Lee   1324944
[2] “Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana.”  Hamelmann   11439000
[3] “Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants.”  Gasmelseed   14722929
[4] “GJB2 mutations: passage through Iran.”  Najmabadi   15666300
[5] “The DNA sequence and analysis of human chromosome 13.”  Dunham   15057823
[6] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project   15489334
[7] “A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment.”  del Castillo   15994881
[8] “Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.”  Kelsell   9139825
[9] “Connexin mutations and hearing loss.”  Scott   9422505
[10] “Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations.”  Carrasquillo   9328482
[11] “Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene.”  Denoyelle   9336442
[12] “Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.”  Kelley   9529365
[13] “Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.”  Richard   9856479
[14] “Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss.”  Scott   9600457
[15] “Connexin 26 gene linked to a dominant deafness.”  Denoyelle   9620796
[16] “Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa.”  Brobby   9471561
[17] “A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.”  Maestrini   10369869
[18] “Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population.”  Kudo   10607953
[19] “Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.”  Kelsell   10757647
[20] “High frequency hearing loss correlated with mutations in the GJB2 gene.”  Wilcox   10830906
[21] “A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).”  Heathcote   10633135
[22] “A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss.”  Morle   10807696
[23] “Sensorineural hearing loss and the incidence of Cx26 mutations in Austria.”  Loffler   11313763
[24] “Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.”  Richard   11912510
[25] “Exploring the clinical and epidemiological complexity of GJB2-linked deafness.”  Gualandi   12239718
[26] “HID and KID syndromes are associated with the same connexin 26 mutation.”  van Geel   12072059
[27] “Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss.”  Bason   12121355
[28] “The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family.”  Uyguner   12372058
[29] “De novo mutation in the gene encoding connexin-26 (GJB2) in a sporadic case of keratitis-ichthyosis-deafness (KID) syndrome.”  Alvarez   12548749
[30] “Novel mutations in GJB2 encoding connexin-26 in Japanese patients with keratitis-ichthyosis-deafness syndrome.”  Yotsumoto   12752120
[31] “A novel dominant missense mutation -- D179N -- in the GJB2 gene (connexin 26) associated with non-syndromic hearing loss.”  Primignani   12786758
[32] “GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation.”  Ohtsuka   12560944
[33] “Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30.”  Marziano   12668604
[34] “Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India.”  Ramshankar   12746422
[35] “Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2.”  Richard   15482471
[36] “G59S mutation in the GJB2 (connexin 26) gene in a patient with Bart-Pumphrey syndrome.”  Alexandrino   15952212
[37] “Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss.”  Piazza   15996214
[38] “Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness.”  Beltramello   15592461
[39] “M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance.”  Pollak   17935238
[40] “A novel hearing-loss-related mutation occurring in the GJB2 basal promoter.”  Matos   17660464
[41] “A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness.”  de Zwart-Storm   17993581
[42] “Connexin mutations in Brazilian patients with skin disorders with or without hearing loss.”  Alexandrino   19283857
[43] “Novel mutation p.Gly59Arg in GJB6 encoding connexin 30 underlies palmoplantar keratoderma with pseudoainhum, knuckle pads and hearing loss.”  Nemoto-Hasebe   19416251
[44] “Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss.”  Choi   19384972
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