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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:P08034
Protein Name:Cx32 aka Gap junction beta-1 protein
Molecular Weight:32025.00
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: P08034
eggNOG: prNOG16944
RefSeq: NP_000157.1    NP_001091111.1   
Entrez Gene ID: 2705   
Pfam: PF00029    PF10582   
OMIM: 145900  phenotype
302800  phenotype
304040  gene
KEGG: hsa:2705   

Gene Ontology

GO:0005922 C:connexon complex
GO:0005789 C:endoplasmic reticulum membrane
GO:0016021 C:integral to membrane
GO:0005243 F:gap junction channel activity
GO:0007267 P:cell-cell signaling
GO:0007399 P:nervous system development

References (66)

[1] “Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein.”  Kumar   2875078
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota   14702039
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project   15489334
[4] “Topology of the 32-kd liver gap junction protein determined by site-directed antibody localizations.”  Milks   2460334
[5] “A Calpha model for the transmembrane alpha helices of gap junction intercellular channels.”  Fleishman   15383278
[6] “Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies.”  Nelis   9888385
[7] “Connexin mutations in X-linked Charcot-Marie-Tooth disease.”  Bergoffen   8266101
[8] “Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).”  Fairweather   8162049
[9] “Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy.”  Ionasescu   8004109
[10] “X-linked dominant Charcot-Marie-Tooth neuropathy: valine-38-methionine substitution of connexin32.”  Orth   7833935
[11] “New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.”  Bone   7477983
[12] “Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy.”  Ionasescu   8737658
[13] “X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene.”  Ressot   8698335
[14] “Novel mutations in the connexin 32 gene associated with X-linked Charcot-Marie tooth disease.”  Tan   8829637
[15] “Novel missense mutation of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy.”  Schiavon   8807343
[16] “Two novel mutations (C53S, S26L) in the connexin32 of Charcot-Marie-Tooth disease type X families.”  Yoshimura   8889588
[17] “A point mutation in codon 3 of connexin-32 is associated with X-linked Charcot-Marie-Tooth neuropathy.”  Gupta   8956046
[18] “Arginine-164-tryptophan substitution in connexin32 associated with X linked dominant Charcot-Marie-Tooth disease.”  Oterino   8733054
[19] “Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type 2 families with chromosomes 1p35-p36 and Xq13.”  Timmerman   8628473
[20] “New mutations in the X-linked form of Charcot-Marie-Tooth disease.”  Latour   9018031
[21] “Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).”  Janssen   9099841
[22] “Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies.”  Bort   9187667
[23] “Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance.”  Silander   9272161
[24] “Mutation analysis of the connexin 32 (Cx32) gene in Charcot-Marie-Tooth neuropathy type 1: identification of five new mutations.”  Nelis   8990008
[25] “Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families.”  Rouger   9401007
[26] “Connexin32 and X-linked Charcot-Marie-Tooth disease.”  Bone   9361298
[27] “Mutations in the X-linked form of Charcot-Marie-Tooth disease in the French population.”  Latour   10732813
[28] “Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1.”  Ikegami   9856562
[29] “X-linked Charcot-Marie-Tooth disease and connexin32.”  Ionasescu   10873293
[30] “A novel mutation (C201R) in the transmembrane domain of connexin 32 in severe X-linked Charcot-Marie-Tooth disease.”  Sillen   9452025
[31] “Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1).”  Sorour   9452099
[32] “Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease and related neuropathies.”  Silander   9633821
[33] “Mutations of connexin32 in Charcot-Marie-Tooth disease type X interfere with cell-to-cell communication but not cell proliferation and myelin-specific gene expression.”  Yoshimura   9469569
[34] “Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations.”  Nicholson   9818870
[35] “HMSN and HNPP. Laboratory service provision in the south west of England -- two years' experience.”  Williams   10586284
[36] “Three novel mutations in the gap junction beta 1 (GJB1) gene coding region identified in Charcot-Marie-Tooth patients of Greek origin: T55I, R164Q, V120E.”  Karadimas   10220155
[37] “Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene.”  Baehr   10071100
[38] “Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations.”  Castro   10234007
[39] “Mutational analysis and genotype/phenotype correlation in Turkish Charcot-Marie-Tooth type 1 and HNPP patients.”  Bissar-Tadmouri   11140841
[40] “A family with X-linked dominant Charcot-Marie-Tooth caused by a connexin32 mutation.”  Verhelst   11030070
[41] “Severe X-linked Charcot-Marie-Tooth neuropathy due to new mutations [G59R(G-->C), W44X(G-->A)] in the connexin 32 gene.”  Felice   10894999
[42] “Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients.”  Mersiyanova   10737979
[43] “Mutations in the peripheral myelin protein zero and connexin32 genes detected by non-isotopic RNase cleavage assay and their phenotypes in Japanese patients with Charcot-Marie-Tooth disease.”  Yoshihara   10923043
[44] “A new de novo mutation of the connexin-32 gene in a patient with X-linked Charcot-Marie-Tooth type 1 disease.”  Di Iorio   10938190
[45] “Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.”  Dubourg   11571214
[46] “A novel connexin 32 missense mutation (E208G) causing Charcot-Marie-Tooth disease.”  Kochanski   11180613
[47] “Charcot-Marie-Tooth disease type I and related demyelinating neuropathies: mutation analysis in a large cohort of Italian families.”  Mostacciuolo   11438991
[48] “Charcot-Marie-Tooth type X: a novel mutation in the Cx32 gene with central conduction slowing.”  Seeman   11562788
[49] “Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity.”  Young   11437164
[50] “Episodes of generalized weakness in two sibs with the C164T mutation of the connexin 32 gene.”  Panas   11723288
[51] “Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.”  Boerkoel   11835375
[52] “Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease.”  Paulson   12325071
[53] “Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease: DGGE analysis for PMP22, MPZ, and Cx32/GJB1 mutations.”  Numakura   12402337
[54] “Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease.”  Lee   12185164
[55] “Diverse trafficking abnormalities of connexin32 mutants causing CMTX.”  Yum   12460545
[56] “X-linked Charcot-Marie-Tooth disease caused by a novel point mutation in the connexin-32 gene.”  Ma   12536289
[57] “Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.”  Street   12207932
[58] “Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease.”  Abrams   11891346
[59] “Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation.”  Hanemann   12707076
[60] “Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients.”  Hattori   12477701
[61] “Novel mutations in the Charcot-Marie-Tooth disease genes PMP22, MPZ, and GJB1.”  Huehne   12497641
[62] “Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32.”  Abrams   14627639
[63] “Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients.”  Choi   15241803
[64] “Severe neuropathy with leaky connexin32 hemichannels.”  Liang   15852376
[65] “X-linked Charcot-Marie-Tooth disease: phenotypic expression of a novel mutation Ile127Ser in the GJB1 (connexin 32) gene.”  Vondracek   15468313
[66] “Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family.”  Chung   15947997

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