5kj3

Structural highlights

Disease

[CXB2_HUMAN] KID syndrome;Knuckle pads - leuconychia - sensorineural deafness;Autosomal dominant nonsyndromic sensorineural deafness type DFNA;Autosomal recessive nonsyndromic sensorineural deafness type DFNB;Palmoplantar keratoderma - deafness;Keratoderma hereditarium mutilans. Defects in GJB2 are the cause of deafness autosomal recessive type 1A (DFNB1A) [MIM:220290]. DFNB1A is a form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]} Defects in GJB2 are the cause of deafness autosomal dominant type 3A (DFNA3A) [MIM:601544]. Defects in GJB2 are a cause of Vohwinkel syndrome (VS) [MIM:124500]. VS is an autosomal dominant disease characterized by hyperkeratosis, constriction on finger and toes and congenital deafness.^{[17] [18]} Defects in GJB2 are a cause of palmoplantar keratoderma with deafness (PPKDFN) [MIM:148350]. PPKDFN is an autosomal dominant disorder characterized by the association of palmoplantar hyperkeratosis with progressive, bilateral, high-frequency, sensorineural deafness.^{[19] [20] [21] [22] [23] [24] [25]} Defects in GJB2 are a cause of keratitis-ichthyosis-deafness syndrome (KID syndrome) [MIM:148210]; an autosomal dominant form of ectodermal dysplasia. Ectodermal dysplasias (EDs) constitute a heterogeneous group of developmental disorders affecting tissues of ectodermal origin. EDs are characterized by abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. KID syndrome is characterized by the association of hyperkeratotic skin lesions with vascularizing keratitis and profound sensorineural hearing loss. Clinical features include deafness, ichthyosis, photobia, absent or decreased eyebrows, sparse or absent scalp hair, decreased sweating and dysplastic finger and toenails. Defects in GJB2 are the cause of Bart-Pumphrey syndrome (BPS) [MIM:149200]. BPS is an autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, It shows considerable phenotypic variability.^{[26] [27]} Defects in GJB2 are the cause of ichthyosis hystrix-like with deafness syndrome (HID syndrome) [MIM:602540]. HID syndrome is an autosomal-dominant inherited keratinizing disorder characterized by sensorineural deafness and spiky hyperkeratosis affecting the entire skin. HID syndrome is considered to differ from the similar KID syndrome in the extent and time of occurrence of skin symptoms and the severity of the associated keratitis.

Function

[CXB2_HUMAN] One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

References

1. ↑ Hamelmann C, Amedofu GK, Albrecht K, Muntau B, Gelhaus A, Brobby GW, Horstmann RD. Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. Hum Mutat. 2001;18(1):84-5. PMID:11439000 doi:10.1002/humu.1155
2. ↑ Gasmelseed NM, Schmidt M, Magzoub MM, Macharia M, Elmustafa OM, Ototo B, Winkler E, Ruge G, Horstmann RD, Meyer CG. Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants. Hum Mutat. 2004 Feb;23(2):206-7. PMID:14722929 doi:10.1002/humu.9216
3. ↑ Najmabadi H, Nishimura C, Kahrizi K, Riazalhosseini Y, Malekpour M, Daneshi A, Farhadi M, Mohseni M, Mahdieh N, Ebrahimi A, Bazazzadegan N, Naghavi A, Avenarius M, Arzhangi S, Smith RJ. GJB2 mutations: passage through Iran. Am J Med Genet A. 2005 Mar 1;133A(2):132-7. PMID:15666300 doi:10.1002/ajmg.a.30576
4. ↑ del Castillo FJ, Rodriguez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E, de Oliveira CA, Azaiez H, Brownstein Z, Avenarius MR, Marlin S, Pandya A, Shahin H, Siemering KR, Weil D, Wuyts W, Aguirre LA, Martin Y, Moreno-Pelayo MA, Villamar M, Avraham KB, Dahl HH, Kanaan M, Nance WE, Petit C, Smith RJ, Van Camp G, Sartorato EL, Murgia A, Moreno F, del Castillo I. 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. J Med Genet. 2005 Jul;42(7):588-94. PMID:15994881 doi:10.1136/jmg.2004.028324
5. ↑ Carrasquillo MM, Zlotogora J, Barges S, Chakravarti A. Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations. Hum Mol Genet. 1997 Nov;6(12):2163-72. PMID:9328482
6. ↑ Denoyelle F, Weil D, Maw MA, Wilcox SA, Lench NJ, Allen-Powell DR, Osborn AH, Dahl HH, Middleton A, Houseman MJ, Dode C, Marlin S, Boulila-ElGaied A, Grati M, Ayadi H, BenArab S, Bitoun P, Lina-Granade G, Godet J, Mustapha M, Loiselet J, El-Zir E, Aubois A, Joannard A, Petit C, et al.. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997 Nov;6(12):2173-7. PMID:9336442
7. ↑ Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet. 1998 Apr;62(4):792-9. PMID:9529365 doi:S0002-9297(07)60970-7
8. ↑ Brobby GW, Muller-Myhsok B, Horstmann RD. Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa. N Engl J Med. 1998 Feb 19;338(8):548-50. PMID:9471561 doi:10.1056/NEJM199802193380813
9. ↑ Wilcox SA, Saunders K, Osborn AH, Arnold A, Wunderlich J, Kelly T, Collins V, Wilcox LJ, McKinlay Gardner RJ, Kamarinos M, Cone-Wesson B, Williamson R, Dahl HH. High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet. 2000 Apr;106(4):399-405. PMID:10830906
10. ↑ Loffler J, Nekahm D, Hirst-Stadlmann A, Gunther B, Menzel HJ, Utermann G, Janecke AR. Sensorineural hearing loss and the incidence of Cx26 mutations in Austria. Eur J Hum Genet. 2001 Mar;9(3):226-30. PMID:11313763 doi:10.1038/sj.ejhg.5200607
11. ↑ Gualandi F, Ravani A, Berto A, Sensi A, Trabanelli C, Falciano F, Trevisi P, Mazzoli M, Tibiletti MG, Cristofari E, Burdo S, Ferlini A, Martini A, Calzolari E. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet. 2002 Sep 15;112(1):38-45. PMID:12239718 doi:10.1002/ajmg.10621
12. ↑ Bason L, Dudley T, Lewis K, Shah U, Potsic W, Ferraris A, Fortina P, Rappaport E, Krantz ID. Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss. Clin Genet. 2002 Jun;61(6):459-64. PMID:12121355
13. ↑ Primignani P, Castorina P, Sironi F, Curcio C, Ambrosetti U, Coviello DA. A novel dominant missense mutation--D179N--in the GJB2 gene (Connexin 26) associated with non-syndromic hearing loss. Clin Genet. 2003 Jun;63(6):516-21. PMID:12786758
14. ↑ Beltramello M, Piazza V, Bukauskas FF, Pozzan T, Mammano F. Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol. 2005 Jan;7(1):63-9. Epub 2004 Dec 12. PMID:15592461 doi:10.1038/ncb1205
15. ↑ Matos TD, Caria H, Simoes-Teixeira H, Aasen T, Nickel R, Jagger DJ, O'Neill A, Kelsell DP, Fialho G. A novel hearing-loss-related mutation occurring in the GJB2 basal promoter. J Med Genet. 2007 Nov;44(11):721-5. Epub 2007 Jul 27. PMID:17660464 doi:10.1136/jmg.2007.050682
16. ↑ Choi SY, Park HJ, Lee KY, Dinh EH, Chang Q, Ahmad S, Lee SH, Bok J, Lin X, Kim UK. Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss. Hum Mutat. 2009 Jul;30(7):E716-27. doi: 10.1002/humu.21036. PMID:19384972 doi:10.1002/humu.21036
17. ↑ Marziano NK, Casalotti SO, Portelli AE, Becker DL, Forge A. Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Hum Mol Genet. 2003 Apr 15;12(8):805-12. PMID:12668604
18. ↑ Maestrini E, Korge BP, Ocana-Sierra J, Calzolari E, Cambiaghi S, Scudder PM, Hovnanian A, Monaco AP, Munro CS. A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families. Hum Mol Genet. 1999 Jul;8(7):1237-43. PMID:10369869
19. ↑ Marziano NK, Casalotti SO, Portelli AE, Becker DL, Forge A. Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Hum Mol Genet. 2003 Apr 15;12(8):805-12. PMID:12668604
20. ↑ Richard G, White TW, Smith LE, Bailey RA, Compton JG, Paul DL, Bale SJ. Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. Hum Genet. 1998 Oct;103(4):393-9. PMID:9856479
21. ↑ Kelsell DP, Wilgoss AL, Richard G, Stevens HP, Munro CS, Leigh IM. Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family. Eur J Hum Genet. 2000 Feb;8(2):141-4. PMID:10757647 doi:10.1038/sj.ejhg.5200407
22. ↑ Heathcote K, Syrris P, Carter ND, Patton MA. A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350). J Med Genet. 2000 Jan;37(1):50-1. PMID:10633135
23. ↑ Uyguner O, Tukel T, Baykal C, Eris H, Emiroglu M, Hafiz G, Ghanbari A, Baserer N, Yuksel-Apak M, Wollnik B. The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family. Clin Genet. 2002 Oct;62(4):306-9. PMID:12372058
24. ↑ Piazza V, Beltramello M, Menniti M, Colao E, Malatesta P, Argento R, Chiarella G, Gallo LV, Catalano M, Perrotti N, Mammano F, Cassandro E. Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss. Clin Genet. 2005 Aug;68(2):161-6. PMID:15996214 doi:10.1111/j.1399-0004.2005.00468.x
25. ↑ de Zwart-Storm EA, Hamm H, Stoevesandt J, Steijlen PM, Martin PE, van Geel M, van Steensel MA. A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness. J Med Genet. 2008 Mar;45(3):161-6. Epub 2007 Nov 9. PMID:17993581 doi:10.1136/jmg.2007.052332
26. ↑ Richard G, Brown N, Ishida-Yamamoto A, Krol A. Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2. J Invest Dermatol. 2004 Nov;123(5):856-63. PMID:15482471 doi:10.1111/j.0022-202X.2004.23470.x
27. ↑ Alexandrino F, Sartorato EL, Marques-de-Faria AP, Steiner CE. G59S mutation in the GJB2 (connexin 26) gene in a patient with Bart-Pumphrey syndrome. Am J Med Genet A. 2005 Jul 30;136(3):282-4. PMID:15952212 doi:10.1002/ajmg.a.30822
28. ↑ Batir Y, Bargiello TA, Dowd TL. Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using (1)H NMR spectroscopy. Arch Biochem Biophys. 2016 Oct 15;608:8-19. doi: 10.1016/j.abb.2016.06.019. Epub , 2016 Jul 1. PMID:27378082 doi:http://dx.doi.org/10.1016/j.abb.2016.06.019