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1.A.24.1.3
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
Length:226
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 S.W.et.al.   1324944
[2] “Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana.”  Hamelmann C.et.al.   11439000
[3] “Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants.”  Gasmelseed N.M.A.et.al.   14722929
[4] “GJB2 mutations: passage through Iran.”  Najmabadi H.et.al.   15666300
[5] “The DNA sequence and analysis of human chromosome 13.”  Dunham A.et.al.   15057823
[6] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   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 F.J.et.al.   15994881
[8] “Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.”  Kelsell D.P.et.al.   9139825
[9] “Connexin mutations and hearing loss.”  Scott D.A.et.al.   9422505
[10] “Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations.”  Carrasquillo M.M.et.al.   9328482
[11] “Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene.”  Denoyelle F.et.al.   9336442
[12] “Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.”  Kelley P.M.et.al.   9529365
[13] “Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.”  Richard G.et.al.   9856479
[14] “Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss.”  Scott D.A.et.al.   9600457
[15] “Connexin 26 gene linked to a dominant deafness.”  Denoyelle F.et.al.   9620796
[16] “Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa.”  Brobby G.W.et.al.   9471561
[17] “A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.”  Maestrini E.et.al.   10369869
[18] “Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population.”  Kudo T.et.al.   10607953
[19] “Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.”  Kelsell D.P.et.al.   10757647
[20] “High frequency hearing loss correlated with mutations in the GJB2 gene.”  Wilcox S.A.et.al.   10830906
[21] “A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).”  Heathcote K.et.al.   10633135
[22] “A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss.”  Morle L.et.al.   10807696
[23] “Sensorineural hearing loss and the incidence of Cx26 mutations in Austria.”  Loffler J.et.al.   11313763
[24] “Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.”  Richard G.et.al.   11912510
[25] “Exploring the clinical and epidemiological complexity of GJB2-linked deafness.”  Gualandi F.et.al.   12239718
[26] “HID and KID syndromes are associated with the same connexin 26 mutation.”  van Geel M.et.al.   12072059
[27] “Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss.”  Bason L.et.al.   12121355
[28] “The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family.”  Uyguner O.et.al.   12372058
[29] “De novo mutation in the gene encoding connexin-26 (GJB2) in a sporadic case of keratitis-ichthyosis-deafness (KID) syndrome.”  Alvarez A.et.al.   12548749
[30] “Novel mutations in GJB2 encoding connexin-26 in Japanese patients with keratitis-ichthyosis-deafness syndrome.”  Yotsumoto S.et.al.   12752120
[31] “A novel dominant missense mutation -- D179N -- in the GJB2 gene (connexin 26) associated with non-syndromic hearing loss.”  Primignani P.et.al.   12786758
[32] “GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation.”  Ohtsuka A.et.al.   12560944
[33] “Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30.”  Marziano N.K.et.al.   12668604
[34] “Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India.”  Ramshankar M.et.al.   12746422
[35] “Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2.”  Richard G.et.al.   15482471
[36] “G59S mutation in the GJB2 (connexin 26) gene in a patient with Bart-Pumphrey syndrome.”  Alexandrino F.et.al.   15952212
[37] “Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss.”  Piazza V.et.al.   15996214
[38] “Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness.”  Beltramello M.et.al.   15592461
[39] “M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance.”  Pollak A.et.al.   17935238
[40] “A novel hearing-loss-related mutation occurring in the GJB2 basal promoter.”  Matos T.D.et.al.   17660464
[41] “A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness.”  de Zwart-Storm E.A.et.al.   17993581
[42] “Connexin mutations in Brazilian patients with skin disorders with or without hearing loss.”  Alexandrino F.et.al.   19283857
[43] “Novel mutation p.Gly59Arg in GJB6 encoding connexin 30 underlies palmoplantar keratoderma with pseudoainhum, knuckle pads and hearing loss.”  Nemoto-Hasebe I.et.al.   19416251
[44] “Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss.”  Choi S.-Y.et.al.   19384972
Structure:
1XIR   2ZW3   3IZ1   3IZ2   5er7     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MDWGTLQTIL GGVNKHSTSI GKIWLTVLFI FRIMILVVAA KEVWGDEQAD FVCNTLQPGC 
61:	KNVCYDHYFP ISHIRLWALQ LIFVSTPALL VAMHVAYRRH EKKRKFIKGE IKSEFKDIEE 
121:	IKTQKVRIEG SLWWTYTSSI FFRVIFEAAF MYVFYVMYDG FSMQRLVKCN AWPCPNTVDC 
181:	FVSRPTEKTV FTVFMIAVSG ICILLNVTEL CYLLIRYCSG KSKKPV