GJB6

GJB6
Identifiers
AliasesGJB6, CX30, DFNA3, DFNA3B, DFNB1B, ECTD2, ED2, EDH, HED, HED2, gap junction protein beta 6
External IDsMGI: 107588 HomoloGene: 4936 GeneCards: GJB6
Gene location (Human)
Chr.Chromosome 13 (human)[1]
Band13q12.11Start20,221,962 bp[1]
End20,232,395 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

10804

14623

Ensembl

ENSG00000121742

ENSMUSG00000040055

UniProt

O95452

P70689

RefSeq (mRNA)

NM_006783
NM_001110219
NM_001110220
NM_001110221

NM_001010937
NM_001271663
NM_008128

RefSeq (protein)

NP_001103689
NP_001103690
NP_001103691
NP_006774

NP_001010937
NP_001258592

Location (UCSC)Chr 13: 20.22 – 20.23 MbChr 14: 57.12 – 57.13 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gap junction beta-6 protein (GJB6), also known as connexin 30 (Cx30) — is a protein that in humans is encoded by the GJB6 gene.[5][6][7] Connexin 30 (Cx30) is one of several gap junction proteins expressed in the inner ear.[8] Mutations in gap junction genes have been found to lead to both syndromic and nonsyndromic deafness.[9] Mutations in this gene are associated with Clouston syndrome (i.e., hydrotic ectodermal dysplasia).

Function

The connexin gene family codes for the protein subunits of gap junction channels that mediate direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Connexins span the plasma membrane 4 times, with amino- and carboxy-terminal regions facing the cytoplasm. Connexin genes are expressed in a cell type-specific manner with overlapping specificity. The gap junction channels have unique properties depending on the type of connexins constituting the channel.[supplied by OMIM][7]

Connexin 30 is prevalent in the two distinct gap junction systems found in the cochlea: the epithelial cell gap junction network, which couple non-sensory epithelial cells, and the connective tissue gap junction network, which couple connective tissue cells. Gap junctions serve the important purpose of recycling potassium ions that pass through hair cells during mechanotransduction back to the endolymph.[10]

Connexin 30 has been found to be co-localized with connexin 26.[11] Cx30 and Cx26 have also been found to form heteromeric and heterotypic channels. The biochemical properties and channel permeabilities of these more complex channels differ from homotypic Cx30 or Cx26 channels.[12] Overexpression of Cx30 in Cx30 null mice restored Cx26 expression and normal gap junction channel functioning and calcium signaling, but it is described that Cx26 expression is altered in Cx30 null mice. The researchers hypothesized that co-regulation of Cx26 and Cx30 is dependent on phospholipase C signaling and the NF-κB pathway.[13]

The cochlea contains two cell types, auditory hair cells for mechanotransduction and supporting cells. Gap junction channels are only found between cochlear supporting cells.[14] While gap junctions in the inner ear are critically involved in potassium recycling to the endolymph, connexin expression in the supporting cells surrounding the organ of Corti have been found to support epithelial tissue lesion repair following loss of sensory hair cells. An experiment with Cx30 null mice found deficits in lesion closure and repair of the organ of Corti following hair cell loss, suggesting that Cx30 has a role in regulating lesion repair response.[15]

Clinical Significance

Auditory

Connexin 26 and connexin 30 are commonly accepted to be the predominant gap junction proteins in the cochlea. Genetic knockout experiments in mice has shown that knockout of either Cx26 or Cx30 produces deafness.[16][17] However, recent research suggests that Cx30 knockout produces deafness due to subsequent downregulation of Cx26, and one mouse study found that a Cx30 mutation that preserves half of Cx26 expression found in normal Cx30 mice resulted in unimpaired hearing.[18] The lessened severity of Cx30 knockout in comparison to Cx26 knockout is supported by a study examining the time course and patterns of hair cell degeneration in the cochlea. Cx26 null mice displayed more rapid and widespread cell death than Cx30 null mice. The percent hair cell loss was less widespread and frequent in the cochleas of Cx30 null mice.[19]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000121742 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040055 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Grifa A, Wagner CA, D'Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, Rabionet R, Arbones M, Monica MD, Estivill X, Zelante L, Lang F, Gasparini P (September 1999). "Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus". Nature Genetics. 23 (1): 16–8. doi:10.1038/12612. PMID 10471490.
  6. ↑ Kibar Z, Der Kaloustian VM, Brais B, Hani V, Fraser FC, Rouleau GA (April 1996). "The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q". Human Molecular Genetics. 5 (4): 543–7. doi:10.1093/hmg/5.4.543. PMID 8845850.
  7. 1 2 "Entrez Gene: GJB6 gap junction protein, beta 6".
  8. ↑ Zhao HB, Kikuchi T, Ngezahayo A, White TW (2006). "Gap junctions and cochlear homeostasis". The Journal of Membrane Biology. 209 (2–3): 177–86. doi:10.1007/s00232-005-0832-x. PMC 1609193. PMID 16773501.
  9. ↑ Erbe CB, Harris KC, Runge-Samuelson CL, Flanary VA, Wackym PA (April 2004). "Connexin 26 and connexin 30 mutations in children with nonsyndromic hearing loss". The Laryngoscope. 114 (4): 607–11. doi:10.1097/00005537-200404000-00003. PMID 15064611.
  10. ↑ Kikuchi T, Kimura RS, Paul DL, Takasaka T, Adams JC (April 2000). "Gap junction systems in the mammalian cochlea". Brain Research. Brain Research Reviews. 32 (1): 163–6. doi:10.1016/S0165-0173(99)00076-4. PMID 10751665.
  11. ↑ Lautermann J, ten Cate WJ, Altenhoff P, Grümmer R, Traub O, Frank H, Jahnke K, Winterhager E (December 1998). "Expression of the gap-junction connexins 26 and 30 in the rat cochlea". Cell and Tissue Research. 294 (3): 415–20. doi:10.1007/s004410051192. PMID 9799458.
  12. ↑ Yum SW, Zhang J, Valiunas V, Kanaporis G, Brink PR, White TW, Scherer SS (September 2007). "Human connexin26 and connexin30 form functional heteromeric and heterotypic channels". American Journal of Physiology. Cell Physiology. 293 (3): C1032–48. doi:10.1152/ajpcell.00011.2007. PMID 17615163.
  13. ↑ Ortolano S, Di Pasquale G, Crispino G, Anselmi F, Mammano F, Chiorini JA (December 2008). "Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear". Proceedings of the National Academy of Sciences of the United States of America. 105 (48): 18776–81. doi:10.1073/pnas.0800831105. PMC 2596232. PMID 19047647.
  14. ↑ Kikuchi T, Kimura RS, Paul DL, Adams JC (February 1995). "Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis". Anatomy and Embryology. 191 (2): 101–18. doi:10.1007/BF00186783. PMID 7726389.
  15. ↑ Forge A, Jagger DJ, Kelly JJ, Taylor RR (April 2013). "Connexin30-mediated intercellular communication plays an essential role in epithelial repair in the cochlea". Journal of Cell Science. 126 (Pt 7): 1703–12. doi:10.1242/jcs.125476. PMID 23424196.
  16. ↑ Teubner B, Michel V, Pesch J, Lautermann J, Cohen-Salmon M, Söhl G, Jahnke K, Winterhager E, Herberhold C, Hardelin JP, Petit C, Willecke K (January 2003). "Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential". Human Molecular Genetics. 12 (1): 13–21. doi:10.1093/hmg/ddg001. PMID 12490528.
  17. ↑ Kudo T, Kure S, Ikeda K, Xia AP, Katori Y, Suzuki M, Kojima K, Ichinohe A, Suzuki Y, Aoki Y, Kobayashi T, Matsubara Y (May 2003). "Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness". Human Molecular Genetics. 12 (9): 995–1004. doi:10.1093/hmg/ddg116. PMID 12700168.
  18. ↑ Boulay AC, del Castillo FJ, Giraudet F, Hamard G, Giaume C, Petit C, Avan P, Cohen-Salmon M (January 2013). "Hearing is normal without connexin30". The Journal of Neuroscience. 33 (2): 430–4. doi:10.1523/JNEUROSCI.4240-12.2013. PMID 23303923.
  19. ↑ Sun Y, Tang W, Chang Q, Wang Y, Kong W, Lin X (October 2009). "Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea". The Journal of Comparative Neurology. 516 (6): 569–79. doi:10.1002/cne.22117. PMC 2846422. PMID 19673007.

Further reading

  • Stoppini M, Bellotti V, Negri A, Merlini G, Garver F, Ferri G (March 1995). "Characterization of the two unique human anti-flavin monoclonal immunoglobulins". European Journal of Biochemistry. 228 (3): 886–93. doi:10.1111/j.1432-1033.1995.tb20336.x. PMID 7737190.
  • Eggena M, Targan SR, Iwanczyk L, Vidrich A, Gordon LK, Braun J (May 1996). "Phage display cloning and characterization of an immunogenetic marker (perinuclear anti-neutrophil cytoplasmic antibody) in ulcerative colitis". Journal of Immunology. 156 (10): 4005–11. PMID 8621942.
  • Radhakrishna U, Blouin JL, Mehenni H, Mehta TY, Sheth FJ, Sheth JJ, Solanki JV, Antonarakis SE (July 1997). "The gene for autosomal dominant hidrotic ectodermal dysplasia (Clouston syndrome) in a large Indian family maps to the 13q11-q12.1 pericentromeric region". American Journal of Medical Genetics. 71 (1): 80–6. doi:10.1002/(SICI)1096-8628(19970711)71:1<80::AID-AJMG15>3.0.CO;2-R. PMID 9215774.
  • Clausen BE, Bridges SL, Lavelle JC, Fowler PG, Gay S, Koopman WJ, Schroeder HW (April 1998). "Clonally-related immunoglobulin VH domains and nonrandom use of DH gene segments in rheumatoid arthritis synovium". Molecular Medicine. 4 (4): 240–57. PMC 2230361. PMID 9606177.
  • Kelley PM, Abe S, Askew JW, Smith SD, Usami S, Kimberling WJ (December 1999). "Human connexin 30 (GJB6), a candidate gene for nonsyndromic hearing loss: molecular cloning, tissue-specific expression, and assignment to chromosome 13q12". Genomics. 62 (2): 172–6. doi:10.1006/geno.1999.6002. PMID 10610709.
  • Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ (March 2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3491–6. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
  • Lamartine J, Munhoz Essenfelder G, Kibar Z, Lanneluc I, Callouet E, Laoudj D, Lemaître G, Hand C, Hayflick SJ, Zonana J, Antonarakis S, Radhakrishna U, Kelsell DP, Christianson AL, Pitaval A, Der Kaloustian V, Fraser C, Blanchet-Bardon C, Rouleau GA, Waksman G (October 2000). "Mutations in GJB6 cause hidrotic ectodermal dysplasia". Nature Genetics. 26 (2): 142–4. doi:10.1038/79851. PMID 11017065.
  • Rash JE, Yasumura T, Dudek FE, Nagy JI (March 2001). "Cell-specific expression of connexins and evidence of restricted gap junctional coupling between glial cells and between neurons". The Journal of Neuroscience. 21 (6): 1983–2000. PMC 1804287. PMID 11245683.
  • Lerer I, Sagi M, Ben-Neriah Z, Wang T, Levi H, Abeliovich D (November 2001). "A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non-syndromic deafness: A novel founder mutation in Ashkenazi Jews". Human Mutation. 18 (5): 460. doi:10.1002/humu.1222. PMID 11668644.
  • del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Tellería D, Menéndez I, Moreno F (January 2002). "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment". The New England Journal of Medicine. 346 (4): 243–9. doi:10.1056/NEJMoa012052. PMID 11807148.
  • Smith FJ, Morley SM, McLean WH (March 2002). "A novel connexin 30 mutation in Clouston syndrome". The Journal of Investigative Dermatology. 118 (3): 530–2. doi:10.1046/j.0022-202x.2001.01689.x. PMID 11874494.
  • Pallares-Ruiz N, Blanchet P, Mondain M, Claustres M, Roux AF (January 2002). "A large deletion including most of GJB6 in recessive non syndromic deafness: a digenic effect?". European Journal of Human Genetics. 10 (1): 72–6. doi:10.1038/sj.ejhg.5200762. PMID 11896458.
  • Common JE, Becker D, Di WL, Leigh IM, O'Toole EA, Kelsell DP (November 2002). "Functional studies of human skin disease- and deafness-associated connexin 30 mutations". Biochemical and Biophysical Research Communications. 298 (5): 651–6. doi:10.1016/S0006-291X(02)02517-2. PMID 12419304.
  • Beltramello M, Bicego M, Piazza V, Ciubotaru CD, Mammano F, D'Andrea P (June 2003). "Permeability and gating properties of human connexins 26 and 30 expressed in HeLa cells". Biochemical and Biophysical Research Communications. 305 (4): 1024–33. doi:10.1016/S0006-291X(03)00868-4. PMID 12767933.
  • Zhang XJ, Chen JJ, Yang S, Cui Y, Xiong XY, He PP, Dong PL, Xu SJ, Li YB, Zhou Q, Wang Y, Huang W (June 2003). "A mutation in the connexin 30 gene in Chinese Han patients with hidrotic ectodermal dysplasia". Journal of Dermatological Science. 32 (1): 11–7. doi:10.1016/S0923-1811(03)00033-1. PMID 12788524.
  • Pandya A, Arnos KS, Xia XJ, Welch KO, Blanton SH, Friedman TB, Garcia Sanchez G, Liu MD XZ, Morell R, Nance WE (2004). "Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands". Genetics in Medicine. 5 (4): 295–303. doi:10.1097/01.GIM.0000078026.01140.68. PMID 12865758.
  • Günther B, Steiner A, Nekahm-Heis D, Albegger K, Zorowka P, Utermann G, Janecke A (August 2003). "The 342-kb deletion in GJB6 is not present in patients with non-syndromic hearing loss from Austria". Human Mutation. 22 (2): 180. doi:10.1002/humu.9167. PMID 12872268.
  • Harris, A; Locke, D (2009). Connexins, A Guide. New York: Springer. p. 574. ISBN 978-1-934115-46-6.
  • Smith, Richard JH; Sheffield, Abraham M; Van Camp, Guy (2012-04-19). Nonsyndromic Hearing Loss and Deafness, DFNA3. NBK1536. In GeneReviews
  • Smith, Richard JH; Van Camp, Guy (2014-01-02). Nonsyndromic Hearing Loss and Deafness, DFNB1. NBK1272. In GeneReviews
  • Smith, Richard JH; Shearer, A Eliot; Hildebrand, Michael S; Van Camp, Guy (2014-01-09). Deafness and Hereditary Hearing Loss Overview. NBK1434. In GeneReviews
  • Der Kaloustian, Vazken M (2011-02-03). Hidrotic Ectodermal Dysplasia 2. NBK1200. In Pagon RA, Bird TD, Dolan CR, et al., eds. (1993). GeneReviews™ [Internet]. Seattle WA: University of Washington, Seattle.

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