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Gene Review

GJB4  -  gap junction protein, beta 4, 30.3kDa

Homo sapiens

Synonyms: CX30.3, Connexin-30.3, Cx30.3, EKV, Gap junction beta-4 protein
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Disease relevance of GJB4

  • We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects [1].
  • The skin disease erythrokeratoderma variabilis (EKV) has been shown to be associated with mutations in GJB3 and GJB4 encoding connexin (Cx)31 and Cx30.3, respectively [2].

High impact information on GJB4

  • We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S) [3].
  • Our results show that mutations in the gene for Cx30.3 can be causally involved in EKV and point to genetic heterogeneity of this disorder [4].
  • This mutation concerns a highly conserved phenylalanine, in the third transmembrane region of the Cx30.3 molecule, known to be implicated in the wall formation of the gap-junction pore [4].
  • Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis [5].
  • Northern blot hybridization revealed highly tissue-specific coexpression of the 1.6-kb Cx31.1 mRNA and two Cx30.3 transcripts of 1.9- and 3.2-kb size, predominantly in skin and two related mouse keratinocyte cell lines [6].

Biological context of GJB4

  • In addition to pathogenic mutations, we identified several missense mutations and a 4 bp deletion within the GJB4 coding region, which might represent either inconsequential polymorphisms or recessive mutations [7].
  • Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations [7].
  • Other mutations (R22H, T85P, F137L, F189Y) were located in the transmembrane domains of Cx30.3, and are predicted to hinder regulation of voltage gating or alter the kinetics of channel closure [7].
  • We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation [1].
  • Otherwise, the differences between fishes and mammals can be explained by two gene losses (Cx39.9 and Cx43.4) after the divergence of the Reptilia, and three gene duplications (the generation of Cx26 and 30 from a preCx26/30 sequence, Cx30.3 and 31.1 from a preCx30.3/ 31.1 sequence, and Cx31.3 from an uncertain origin) [8].

Anatomical context of GJB4

  • There is now a considerable overlap with other gap junction disorders and we propose that some cases of erythrokeratodermia variabilis without mutations in either GJB3 or GJB4 but with deafness may be caused by mutations in GJB2 [9].
  • In the skin, Cx31 and Cx30.3 are expressed in the stratum granulosum of the epidermis with a suggested role in late keratinocyte differentiation [2].


  1. A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families. López-Bigas, N., Melchionda, S., Gasparini, P., Borragán, A., Arbonés, M.L., Estivill, X. Hum. Mutat. (2002) [Pubmed]
  2. Clinical and genetic heterogeneity of erythrokeratoderma variabilis. Common, J.E., O'Toole, E.A., Leigh, I.M., Thomas, A., Griffiths, W.A., Venning, V., Grabczynska, S., Peris, Z., Kansky, A., Kelsell, D.P. J. Invest. Dermatol. (2005) [Pubmed]
  3. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Richard, G., Smith, L.E., Bailey, R.A., Itin, P., Hohl, D., Epstein, E.H., DiGiovanna, J.J., Compton, J.G., Bale, S.J. Nat. Genet. (1998) [Pubmed]
  4. Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis. Macari, F., Landau, M., Cousin, P., Mevorah, B., Brenner, S., Panizzon, R., Schorderet, D.F., Hohl, D., Huber, M. Am. J. Hum. Genet. (2000) [Pubmed]
  5. Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. Plantard, L., Huber, M., Macari, F., Meda, P., Hohl, D. Hum. Mol. Genet. (2003) [Pubmed]
  6. Two gap junction genes, connexin 31.1 and 30.3, are closely linked on mouse chromosome 4 and preferentially expressed in skin. Hennemann, H., Dahl, E., White, J.B., Schwarz, H.J., Lalley, P.A., Chang, S., Nicholson, B.J., Willecke, K. J. Biol. Chem. (1992) [Pubmed]
  7. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations. Richard, G., Brown, N., Rouan, F., Van der Schroeff, J.G., Bijlsma, E., Eichenfield, L.F., Sybert, V.P., Greer, K.E., Hogan, P., Campanelli, C., Compton, J.G., Bale, S.J., DiGiovanna, J.J., Uitto, J. J. Invest. Dermatol. (2003) [Pubmed]
  8. The vertebrate connexin family. Cruciani, V., Mikalsen, S.O. Cell. Mol. Life Sci. (2006) [Pubmed]
  9. Further delineation of the hypotrichosis-deafness syndrome. Van Steensel, M.A., Van Geel, M., Steijlen, P.M. European journal of dermatology : EJD. (2005) [Pubmed]
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