GJB6
| GJB6 | |||||||||||||||||||||||||
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| Aliasi | GJB6 | ||||||||||||||||||||||||
| Vanjski ID-jevi | OMIM: 604418 MGI: 107588 HomoloGene: 4936 GeneCards: GJB6 | ||||||||||||||||||||||||
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| Vrste | Čovjek | Miš | |||||||||||||||||||||||
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| Lokacija (UCSC) | Chr 13: 20.22 – 20.23 Mb | Chr 14: 57.36 – 57.37 Mb | |||||||||||||||||||||||
| PubMed pretraga | [3] | [4] | |||||||||||||||||||||||
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Međuprostorni vezni protein beta-6 (GJB6), znan i kao koneksin 30 (Cx30) — je protein koji je kod ljudi kodiran genom GJB6.[5][6][7] Koneksin 30 (Cx30) je jedan od nekoliko spojnih proteina za uspostavljenje međućelijskih veza koji se eksprimira u unutrašnjem uhu.[8] Utvrđeno je da mutacije u genima za ove veze dovode i do sindromske i do nesindromske gluhoće.[9] Mutacije u ovom genu povezane su s Cloustonovim sindromom (tj. hidrotskom ektodermnom displazijom).
Aminokiselinska sekvenca[uredi | uredi izvor]
Dužina polipeptidnog lanca je 261 aminokiselina, a molekulska težina — 30.387 Da.[10]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MDWGTLHTFI | GGVNKHSTSI | GKVWITVIFI | FRVMILVVAA | QEVWGDEQED | ||||
| FVCNTLQPGC | KNVCYDHFFP | VSHIRLWALQ | LIFVSTPALL | VAMHVAYYRH | ||||
| ETTRKFRRGE | KRNDFKDIED | IKKQKVRIEG | SLWWTYTSSI | FFRIIFEAAF | ||||
| MYVFYFLYNG | YHLPWVLKCG | IDPCPNLVDC | FISRPTEKTV | FTIFMISASV | ||||
| ICMLLNVAEL | CYLLLKVCFR | RSKRAQTQKN | HPNHALKESK | QNEMNELISD | ||||
| SGQNAITGFP | S |
- Simboli
C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin
Funkcija[uredi | uredi izvor]
Porodica koneksinskih gena kodira proteinske podjedinice kanala koji spajaju pukotinske međućelijske veze i posreduju u direktnoj difuziji iona i metabolita između citoplazmi susjednih ćelija. Koneksini obuhvataju plazmamembranu četiri puta (vidi sliku), a amino– i karboksi-terminalne regije okrenute su prema citoplazmi. Koneksinski geni eksprimiraju se na specifičan način za ćelijski tip sa preklapajućom specifičnošću. Spojni kanali s razmakom imaju jedinstvena svojstva, ovisno o tipu koneksina koji čine kanal (prema OMIM-u).[7]
Koneksin 30 je rasprostranjen u dva različita sistema spajanja razmaka, koji se nalaze u pužnicama: mreža spoja epitelnih pukotinskih međućelijskih veza koja spaja nesenzorne epitelne ćelije i mreža uskih spojevaa u vezivno tkivo, koja spaja ćelije vezivnog tkiva. Uske veze služe važnoj svrsi recikliranja kalijevih iona koji prolaze kroz trepljaste ćelije tokom mehanotransdukcije nazad u endolimfu.[11]
Koneksin 30 je kolokaliziran s koneksinom 26.[12] Utvrđeno je da Cx30 i Cx26 tvore heteromerne i heterotipske kanale. Biohemijska svojstva i propusnost ovih složenijih kanala razlikuju se od homotipskih kanala Cx30 ili Cx26.[13] Prekomjerna ekspresija Cx30 u null miševima Cx30 obnovila je ekspresiju Cx26, funkcioniranje kanala normalnog razmaka i signalizaciju kalcija, ali je u nul miševa Cx30 ekspresija Cx26 promijenjena. Pretpostavlja se da koregulacija Cx26 i Cx30 ovisi o signalizaciji fosfolipaze C i NF-κB putu.[14]
Pužnica sadrži dva tipa ćelija, slušne trepljaste ćelije za mehanotransdukciju i potporne ćelije. Kanali međuprostornog spajanja nalaze se samo između ćelija koje podržavaju pužnicu.[15] Dok su pukotinske međućelijske veze u unutrašnjem uhu kritično uključene u recikliranje kalija u endolimfi, ekspresija koneksina u potpornim ćelijamama koje okružuju Cortijev organ podupire oporavak lezija epitelnog tkiva nakon gubitka čulnih treplastih ćelija. Eksperiment sa nul miševima Cx30 otkrio je nedostatke u zatvaranju lezija i popravku Cortijevog organa nakon gubitka trepljastih ćelija, što ukazuje da Cx30 ima ulogu u regulaciji odgovora na popravak lezija.[16]
Klinički značaj[uredi | uredi izvor]
Slušni[uredi | uredi izvor]
Koneksin 26 i koneksin 30 općenito su prihvaćeni kao proteini spojeva koji prevladavaju u pužnicama. Eksperimenti s genetičkim nokaut-miševima pokazali su da nokaut ili Cx26 ili Cx30 proizvodi gluhoću.[17][18] Međutim, novija istraživanja sugeriraju da nokaut Cx30 proizvodi gluhoću zbog kasnije regulacije Cx26, a jedno je istraživanje na mišu pokazalo da je mutacija Cx30 koja čuva polovinu ekspresije Cx26 pronađena u normalnih miševa Cx30 rezultirala nesmetanim sluhom.[19] Smanjena ozbiljnost nokauta Cx30 u usporedbi s nokautom Cx26 potkrijepljena je studijom koja je ispitivala vremenski tok i obrasce degeneracije trepljastih ćelija u pužnici. Nx miševi Cx26 pokazali su bržu i raširenu ćelijsku smrt od nultih miševa Cx30. Postotak gubitka trepljastih ćelija bio je manje rasprostranjen i učestao u pužnici null miševa Cx30.[20]
Reference[uredi | uredi izvor]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000121742 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040055 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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 (septembar 1999). "Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus". Nature Genetics. 23 (1): 16–8. doi:10.1038/12612. PMID 10471490.
- ^ 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.
- ^ a b "Entrez Gene: GJB6 gap junction protein, beta 6".
- ^ 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.
- ^ 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.
- ^ "UniProt, O95452". Pristupljeno 11. 9. 2017.
- ^ 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.
- ^ Lautermann J, ten Cate WJ, Altenhoff P, Grümmer R, Traub O, Frank H, Jahnke K, Winterhager E (decembar 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.
- ^ Yum SW, Zhang J, Valiunas V, Kanaporis G, Brink PR, White TW, Scherer SS (septembar 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.
- ^ Ortolano S, Di Pasquale G, Crispino G, Anselmi F, Mammano F, Chiorini JA (decembar 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.
- ^ Kikuchi T, Kimura RS, Paul DL, Adams JC (februar 1995). "Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis". Anatomy and Embryology. 191 (2): 101–18. doi:10.1007/BF00186783. PMID 7726389.
- ^ Forge A, Jagger DJ, Kelly JJ, Taylor RR (april 2013). "Connexin30-mediated intercellular communication plays an essential role in epithelial repair in the cochlea" (PDF). Journal of Cell Science. 126 (Pt 7): 1703–12. doi:10.1242/jcs.125476. PMID 23424196.
- ^ 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 (januar 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.
- ^ Kudo T, Kure S, Ikeda K, Xia AP, Katori Y, Suzuki M, Kojima K, Ichinohe A, Suzuki Y, Aoki Y, Kobayashi T, Matsubara Y (maj 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.
- ^ Boulay AC, del Castillo FJ, Giraudet F, Hamard G, Giaume C, Petit C, Avan P, Cohen-Salmon M (januar 2013). "Hearing is normal without connexin30". The Journal of Neuroscience. 33 (2): 430–4. doi:10.1523/JNEUROSCI.4240-12.2013. PMID 23303923.
- ^ Sun Y, Tang W, Chang Q, Wang Y, Kong W, Lin X (oktobar 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.
Dopunska literatura[uredi | uredi izvor]
- Stoppini M, Bellotti V, Negri A, Merlini G, Garver F, Ferri G (mart 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 (maj 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 (juli 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. doi:10.1007/bf03401921. PMC 2230361. PMID 9606177.
- Kelley PM, Abe S, Askew JW, Smith SD, Usami S, Kimberling WJ (decembar 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 (mart 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 (oktobar 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 (mart 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. doi:10.1523/jneurosci.21-06-01983.2001. PMC 1804287. PMID 11245683.
- Lerer I, Sagi M, Ben-Neriah Z, Wang T, Levi H, Abeliovich D (novembar 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 (januar 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 (mart 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 (januar 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 (novembar 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 (juni 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 (juni 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. str. 574. ISBN 978-1-934115-46-6.
- Smith, Richard JH; Sheffield, Abraham M; Van Camp, Guy (19. 4. 2012). Nonsyndromic Hearing Loss and Deafness, DFNA3. NBK1536. In GeneReviews
- Smith, Richard JH; Van Camp, Guy (2. 1. 2014). Nonsyndromic Hearing Loss and Deafness, DFNB1. NBK1272. In GeneReviews
- Smith, Richard JH; Shearer, A Eliot; Hildebrand, Michael S; Van Camp, Guy (9. 1. 2014). Deafness and Hereditary Hearing Loss Overview. NBK1434. In GeneReviews
- Der Kaloustian, Vazken M (3. 2. 2011). Hidrotic Ectodermal Dysplasia 2. NBK1200. In Pagon RA, Bird TD, Dolan CR, et al., ured. (1993). GeneReviews [Internet]. Seattle WA: University of Washington, Seattle.
Vanjski linkovi[uredi | uredi izvor]