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Gene Review

GJA4  -  gap junction protein, alpha 4, 37kDa

Homo sapiens

Synonyms: CX37, Connexin-37, Cx37, Gap junction alpha-4 protein
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Disease relevance of GJA4


High impact information on GJA4

  • GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval [6].
  • H36.12j macrophages expressing either of the two CX37 proteins encoded by a polymorphism in the human GJA4 gene show differential ATP-dependent adhesion [7].
  • A genetic polymorphism in the human gene encoding connexin37 (CX37, encoded by GJA4, also known as CX37) has been reported as a potential prognostic marker for atherosclerosis [7].
  • Using in vivo adoptive transfer, we show that monocyte and macrophage recruitment is enhanced by eliminating expression of Cx37 in these leukocytes but not by eliminating its expression in the endothelium [7].
  • We further show that Cx37 hemichannel activity in primary monocytes, macrophages and a macrophage cell line (H36.12j) inhibits leukocyte adhesion [7].

Biological context of GJA4


Anatomical context of GJA4


Associations of GJA4 with chemical compounds


Regulatory relationships of GJA4

  • In HeLa cells, SNAP did not reduce dye transfer of cells expressing Cx43, but decreased the dye transfer from Cx37-expressing cells to Cx43-expressing cells by 76% [10].

Other interactions of GJA4

  • After having mapped the disorder to chromosome 1p34-p35, we found no mutations in the genes for Cx31, Cx31.1, and Cx37 [17].
  • Three other connexins (Cx32, Cx37, and Cx40), which are not observed in control interfollicular epidermis, were not induced in either nonlesional or lesional regions of psoriatic skin [18].
  • Among these polymorphisms, those of ICAM1, CNR2, and GJA4 were markedly associated with BMD [5].
  • Cx37 and Cx45 made a large variety of functional heteromeric combinations with Cx43 based on detection of many different single channel conductances [19].
  • CONCLUSIONS: Determination of the genotypes of the connexin 37, plasminogen-activator inhibitor type 1, and stromelysin-1 genes may prove reliable in predicting the genetic risk of myocardial infarction and might thus contribute to the primary prevention of this condition [20].

Analytical, diagnostic and therapeutic context of GJA4

  • The present case control study performed in a homogeneous Caucasoid population confirms the Japanese results that T SNP of Cx37 gene is involved in AMI phenotype, demonstrating the consistency of the association across past studies and across different populations [4].
  • Using two different techniques--injection of a fluorescent dye in single cells as well as detection of the de novo formation of gap junctions by a flow cytometry based technique--we found that NO decreases the functional coupling in Cx37 containing gap junctions whereas it increases the de novo formation of gap junctions containing Cx40 [21].
  • Comparison of the expression of the principal vascular connexins (Cx37, 40 and 43), implicated in EDHF-mediated dilatation were undertaken by immunohistochemistry [22].
  • All Cx37 constructs were produced by the transfected cells as demonstrated by RT-PCR and immunoblotting and trafficked to appositional surfaces between cells as demonstrated by immunofluorescence microscopy [23].
  • Expression of connexin 37, 40, 43, and 45 were detected in As4.1 cells using RT-PCR [24].


  1. Adenoviral delivery of human connexin37 induces endothelial cell death through apoptosis. Seul, K.H., Kang, K.Y., Lee, K.S., Kim, S.H., Beyer, E.C. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  2. Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene. Saito, T., Krutovskikh, V., Marion, M.J., Ishak, K.G., Bennett, W.P., Yamasaki, H. Int. J. Cancer (2000) [Pubmed]
  3. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. Boerma, M., Forsberg, L., Van Zeijl, L., Morgenstern, R., De Faire, U., Lemne, C., Erlinge, D., Thulin, T., Hong, Y., Cotgreave, I.A. J. Intern. Med. (1999) [Pubmed]
  4. Association between C1019T polymorphism of connexin37 and acute myocardial infarction: a study in patients from Sicily. Listì, F., Candore, G., Lio, D., Russo, M., Colonna-Romano, G., Caruso, M., Hoffmann, E., Caruso, C. International journal of cardiology. (2005) [Pubmed]
  5. Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men. Yamada, Y., Ando, F., Shimokata, H. Int. J. Mol. Med. (2007) [Pubmed]
  6. 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]
  7. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Wong, C.W., Christen, T., Roth, I., Chadjichristos, C.E., Derouette, J.P., Foglia, B.F., Chanson, M., Goodenough, D.A., Kwak, B.R. Nat. Med. (2006) [Pubmed]
  8. Genotypes associated with myocardial infarction risk are more common in African Americans than in European Americans. Lanfear, D.E., Marsh, S., Cresci, S., Shannon, W.D., Spertus, J.A., McLeod, H.L. J. Am. Coll. Cardiol. (2004) [Pubmed]
  9. The gene for human gap junction protein connexin37 (GJA4) maps to chromosome 1p35.1, in the vicinity of D1S195. Van Camp, G., Coucke, P., Speleman, F., Van Roy, N., Beyer, E.C., Oostra, B.A., Willems, P.J. Genomics (1995) [Pubmed]
  10. Nitric oxide specifically reduces the permeability of Cx37-containing gap junctions to small molecules. Kameritsch, P., Khandoga, N., Nagel, W., Hundhausen, C., Lidington, D., Pohl, U. J. Cell. Physiol. (2005) [Pubmed]
  11. Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein. Reed, K.E., Westphale, E.M., Larson, D.M., Wang, H.Z., Veenstra, R.D., Beyer, E.C. J. Clin. Invest. (1993) [Pubmed]
  12. Chamber-related differences in connexin expression in the human heart. Vozzi, C., Dupont, E., Coppen, S.R., Yeh, H.I., Severs, N.J. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  13. 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]
  14. Descending vasa recta endothelium is an electrical syncytium. Zhang, Q., Cao, C., Mangano, M., Zhang, Z., Silldorff, E.P., Lee-Kwon, W., Payne, K., Pallone, T.L. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2006) [Pubmed]
  15. In vivo modulation of connexins 43 and 26 of human epidermis by topical retinoic acid treatment. Masgrau-Peya, E., Salomon, D., Saurat, J.H., Meda, P. J. Histochem. Cytochem. (1997) [Pubmed]
  16. The influence of surface charges on the conductance of the human connexin37 gap junction channel. Banach, K., Ramanan, S.V., Brink, P.R. Biophys. J. (2000) [Pubmed]
  17. 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]
  18. Upregulation of connexin 26 between keratinocytes of psoriatic lesions. Labarthe, M.P., Bosco, D., Saurat, J.H., Meda, P., Salomon, D. J. Invest. Dermatol. (1998) [Pubmed]
  19. Heteromeric mixing of connexins: compatibility of partners and functional consequences. Beyer, E.C., Gemel, J., Martínez, A., Berthoud, V.M., Valiunas, V., Moreno, A.P., Brink, P.R. Cell Commun. Adhes. (2001) [Pubmed]
  20. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. Yamada, Y., Izawa, H., Ichihara, S., Takatsu, F., Ishihara, H., Hirayama, H., Sone, T., Tanaka, M., Yokota, M. N. Engl. J. Med. (2002) [Pubmed]
  21. Opposing effects of nitric oxide on different connexins expressed in the vascular system. Kameritsch, P., Hoffmann, A., Pohl, U. Cell Commun. Adhes. (2003) [Pubmed]
  22. The oestrogen receptor {beta} contributes to sex related differences in endothelial function of murine small arteries via EDHF. Luksha, L., Poston, L., Gustafsson, J.A., Hultenby, K., Kublickiene, K. J. Physiol. (Lond.) (2006) [Pubmed]
  23. Functional expression and biophysical properties of polymorphic variants of the human gap junction protein connexin37. Kumari, S.S., Varadaraj, K., Valiunas, V., Ramanan, S.V., Christensen, E.A., Beyer, E.C., Brink, P.R. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  24. Intercellular communication between renin expressing As4.1 cells, endothelial cells and smooth muscle cells. Ryan, M.J., Liu, B., Herbowy, M.T., Gross, K.W., Hajduczok, G. Life Sci. (2003) [Pubmed]
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