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Gene Review

GJA3  -  gap junction protein, alpha 3, 46kDa

Homo sapiens

Synonyms: CTRCT14, CX46, CZP3, Connexin-46, Cx46, ...
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Disease relevance of GJA3

  • CONCLUSIONS: The present study has identified a fifth mutation in GJA3, rendering this connexin gene one of the most common non-crystallin genes associated with autosomal dominant cataracts in humans [1].
  • We have found that ROS 17/2.8 osteosarcoma cells, UMR 106-01 osteosarcoma cells, and primary rat calvarial osteoblastic cells also express another gap junction protein, Cx46 [2].

High impact information on GJA3

  • While Cx43 was assembled into multimeric complexes, ROS cells contained only the monomer form of Cx46 [2].
  • Both rat lens and Hela/Cx46 cells expressed 53-kD (nonphosphorylated) and 68-kD (phosphorylated) forms of Cx46; however, only the 53-kD form was produced by osteoblasts [2].
  • Cx46 is a major component of plasma membrane gap junctions in lens [2].
  • Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3) [3].
  • Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared approximately 88% homology with rat Cx46 [3].

Biological context of GJA3


Anatomical context of GJA3

  • This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens [3].
  • We expressed wild-type Cx46 and the two mutants in Xenopus oocytes [6].
  • Moreover, the strength of junctional coupling among cultured Schwann cells is modulated by a number of cytokines to which Schwann cells are exposed to in vivo after nerve injury, and Cx46 mRNA and protein levels correlate with the degree of coupling [7].
  • In normal rat lung sections, connexin (Cx)32 was expressed by type II cells, whereas Cx43 was more ubiquitously expressed and Cx46 was expressed by occasional alveolar epithelial cells [8].
  • Minimal Cx37 and Cx46 immunoreactivity was detected between occasional atrial or ventricular myocytes [9].

Associations of GJA3 with chemical compounds

  • Sequencing of GJA3 detected a C->T transition in exon 2 that resulted in the gain of an Alu 1 restriction site and was predicted to cause a conservative substitution of proline to leucine at codon 59 (P59L) [1].
  • Sucrose is at the exclusion limit for Cx46 channels whereas sorbitol is at the exclusion limit for Cx32E(1)43 channels [10].
  • Furthermore, a point mutant of Cx46, with leucine substituted by glycine in position 35, displayed a conductance much larger than that of the wild type [11].
  • It is also the first reported cataract-causing mutation in the NH2-terminal region of the Cx46 protein [12].
  • Both Ca(2+) and H(+) play a role in chemical gating of gap junction channels, but, with the possible exception of Cx46 hemichannels, neither of them is likely to induce gating by a direct interaction with connexins [13].

Other interactions of GJA3

  • Individual mutations of Cx46, Cx50 and Cx43 have been found in cataract or heart malformations [14].
  • Substitution of the first extracellular loop (E1) domain of Cx32, an anion-preferring Cx, reduces conductance, converts Cx46 from cation to anion preferring, and changes the I-V relation form inwardly to outwardly rectifying [15].
  • Wild type connexin 46 of rat (wtrCx46), and human connexin 26 (wthCx26) and derivates from rCx46 elongated at the C-terminus by 25 amino acids (rCx46Ct) as well as C-terminal truncated constructs (rCx28.1, rCx45.3) were expressed in frog oocytes of Xenopus laevis [16].
  • Gap junction structures and distribution patterns of immunoreactive connexin46 (Cx46) and connexin50 (Cx50) in normal lenses and lens regrowths of rhesus monkeys were studied using electron microscopy and immunofluorescence double-labeling [17].

Analytical, diagnostic and therapeutic context of GJA3


  1. A novel missense mutation in the gene for gap-junction protein alpha3 (GJA3) associated with autosomal dominant "nuclear punctate" cataracts linked to chromosome 13q. Bennett, T.M., Mackay, D.S., Knopf, H.L., Shiels, A. Mol. Vis. (2004) [Pubmed]
  2. Connexin46 is retained as monomers in a trans-Golgi compartment of osteoblastic cells. Koval, M., Harley, J.E., Hick, E., Steinberg, T.H. J. Cell Biol. (1997) [Pubmed]
  3. Connexin46 mutations in autosomal dominant congenital cataract. Mackay, D., Ionides, A., Kibar, Z., Rouleau, G., Berry, V., Moore, A., Shiels, A., Bhattacharya, S. Am. J. Hum. Genet. (1999) [Pubmed]
  4. A novel mutation in GJA3 (connexin46) for autosomal dominant congenital nuclear pulverulent cataract. Jiang, H., Jin, Y., Bu, L., Zhang, W., Liu, J., Cui, B., Kong, X., Hu, L. Mol. Vis. (2003) [Pubmed]
  5. Novel mutations in GJA3 associated with autosomal dominant congenital cataract in the Indian population. Devi, R.R., Reena, C., Vijayalakshmi, P. Mol. Vis. (2005) [Pubmed]
  6. Connexin46 mutations linked to congenital cataract show loss of gap junction channel function. Pal, J.D., Liu, X., Mackay, D., Shiels, A., Berthoud, V.M., Beyer, E.C., Ebihara, L. Am. J. Physiol., Cell Physiol. (2000) [Pubmed]
  7. Nerve injury and inflammatory cytokines modulate gap junctions in the peripheral nervous system. Chandross, K.J. Glia (1998) [Pubmed]
  8. Heterocellular gap junctional communication between alveolar epithelial cells. Abraham, V., Chou, M.L., George, P., Pooler, P., Zaman, A., Savani, R.C., Koval, M. Am. J. Physiol. Lung Cell Mol. Physiol. (2001) [Pubmed]
  9. Gap junction protein phenotypes of the human heart and conduction system. Davis, L.M., Rodefeld, M.E., Green, K., Beyer, E.C., Saffitz, J.E. J. Cardiovasc. Electrophysiol. (1995) [Pubmed]
  10. Cosegregation of permeability and single-channel conductance in chimeric connexins. Ma, M., Dahl, G. Biophys. J. (2006) [Pubmed]
  11. Conductance of connexin hemichannels segregates with the first transmembrane segment. Hu, X., Ma, M., Dahl, G. Biophys. J. (2006) [Pubmed]
  12. A novel mutation in the connexin 46 gene (GJA3) causes autosomal dominant zonular pulverulent cataract in a Hispanic family. Addison, P.K., Berry, V., Holden, K.R., Espinal, D., Rivera, B., Su, H., Srivastava, A.K., Bhattacharya, S.S. Mol. Vis. (2006) [Pubmed]
  13. Chemical gating of gap junction channels; roles of calcium, pH and calmodulin. Peracchia, C. Biochim. Biophys. Acta (2004) [Pubmed]
  14. Connexin gene mutations in human genetic diseases. Krutovskikh, V., Yamasaki, H. Mutat. Res. (2000) [Pubmed]
  15. The first extracellular loop domain is a major determinant of charge selectivity in connexin46 channels. Trexler, E.B., Bukauskas, F.F., Kronengold, J., Bargiello, T.A., Verselis, V.K. Biophys. J. (2000) [Pubmed]
  16. Length of C-terminus of rCx46 influences oligomerization and hemichannel properties. Zeilinger, C., Steffens, M., Kolb, H.A. Biochim. Biophys. Acta (2005) [Pubmed]
  17. Gap junction structures and distribution patterns of immunoreactive connexins 46 and 50 in lens regrowths of Rhesus monkeys. Lo, W.K., Shaw, A.P., Takemoto, L.J., Grossniklaus, H.E., Tigges, M. Exp. Eye Res. (1996) [Pubmed]
  18. Assignment of connexin 26 (GJB2) and 46 (GJA3) genes to human chromosome 13q11-->q12 and mouse chromosome 14D1-E1 by in situ hybridization. Mignon, C., Fromaget, C., Mattei, M.G., Gros, D., Yamasaki, H., Mesnil, M. Cytogenet. Cell Genet. (1996) [Pubmed]
  19. Effect of external magnesium and calcium on human connexin46 hemichannels. Ebihara, L., Liu, X., Pal, J.D. Biophys. J. (2003) [Pubmed]
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