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Gene Review

CNTN4  -  contactin 4

Homo sapiens

Synonyms: AXCAM, BIG-2, Brain-derived immunoglobulin superfamily protein 2, Contactin-4
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Disease relevance of CNTN4

  • Induction of CNTN4 mRNA expression in human neuroblastoma tumor cells treated with retinoic acid correlated with a block in retinoid-induced neuritogenesis [1].
  • 3. This transcript (also known as BIG-2) is a member of the immunoglobulin super family of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS) [2].
  • This article describes methods used for examining the function of BIG2 including basic protocols, which are not conventional because of cytotoxicity of BIG2 in Escherichia coli cells and its low expression efficiency in mammalian cells [3].
  • These phage Ig-like domains fall into three distinct sequence families, which are similar to the classic immunoglobulin domain (I-Set), the fibronectin type 3 repeat (FN3), and the bacterial Ig-like domain (Big2) [4].

Psychiatry related information on CNTN4


High impact information on CNTN4

  • By electron microscopy, Golgi membranes in BIG1-depleted cells were less sharply defined than those in mock or BIG2 siRNA-treated cells, with more vesicle-like structures at the transface [6].
  • We show here a requirement for BIG1 (but not BIG2) in glycosylation and function of beta1 [6].
  • Association of brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2) with recycling endosomes during transferrin uptake [7].
  • Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2-3p26 [2].
  • Our results demonstrate the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggest a causal relationship [2].

Biological context of CNTN4

  • According to the search of the human genome database, CNTN4 was mapped to 3p25-26, a region very close to the breakpoints of the 3p syndrome [8].
  • The complete nucleotide sequence of CNTN4 is also obtained by combining the insert sequences of two clones, which were isolated when screening the human fetal brain cDNA library with CNTN4A as a probe [8].
  • A novel splice variant of the cell adhesion molecule contactin 4 ( CNTN4) is mainly expressed in human brain [8].
  • Autosomal recessive periventricular heterotopia with microcephaly, a disorder of human embryonic development due to defective vesicular trafficking, has been attributed to mutations in BIG2 [9].
  • To explore possible functions of the N-terminal region of BIG2 (1-832), we used three coding-region constructs as bait to screen a human heart cDNA library in a yeast two-hybrid system, retrieving two unique clones that encode a type I protein kinase A (PKA) regulatory subunit, RI alpha [10].

Anatomical context of CNTN4


Associations of CNTN4 with chemical compounds


Other interactions of CNTN4


Analytical, diagnostic and therapeutic context of CNTN4

  • Western blot analysis of subcellular fractions demonstrated translocation of BIG2 (and BIG1) from cytosol to the Golgi and other membrane structures after incubation of cells with 8-Br-cAMP or forskolin [10].
  • Here, we describe the localization in COS7 cells by immunofluorescence microscopy of BIG2, but not BIG1, with structures that have characteristics of recycling endosomes during transferrin (Tfn) uptake and Tfn receptor (TfnR) recycling [7].
  • When cytosol from HeLa S3 cells was subjected to gel filtration and fractions were analyzed by Western blotting, the largest percentages of both BIG1 and BIG2 were detected in fractions containing proteins with a molecular mass of >670 kDa [15].
  • The interaction between the 110 amino acid C-terminal fragment of BIG2 and the large intracellular loop of the GABA(A)R beta subunits was revealed with a yeast two-hybrid assay [16].


  1. Cloning and characterization of the human neural cell adhesion molecule, CNTN4 (alias BIG-2). Hansford, L.M., Smith, S.A., Haber, M., Norris, M.D., Cheung, B., Marshall, G.M. Cytogenet. Genome Res. (2003) [Pubmed]
  2. Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Fernandez, T., Morgan, T., Davis, N., Klin, A., Morris, A., Farhi, A., Lifton, R.P., State, M.W. Am. J. Hum. Genet. (2004) [Pubmed]
  3. Expression of BIG2 and analysis of its function in mammalian cells. Shin, H.W., Shinotsuka, C., Nakayama, K. Meth. Enzymol. (2005) [Pubmed]
  4. Ig-like domains on bacteriophages: a tale of promiscuity and deceit. Fraser, J.S., Yu, Z., Maxwell, K.L., Davidson, A.R. J. Mol. Biol. (2006) [Pubmed]
  5. FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to mental retardation in 3pter deletions. Dijkhuizen, T., van Essen, T., van der Vlies, P., Verheij, J.B., Sikkema-Raddatz, B., van der Veen, A.Y., Gerssen-Schoorl, K.B., Buys, C.H., Kok, K. Am. J. Med. Genet. A (2006) [Pubmed]
  6. BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein, is required for correct glycosylation and function of integrin beta1. Shen, X., Hong, M.S., Moss, J., Vaughan, M. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  7. Association of brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2) with recycling endosomes during transferrin uptake. Shen, X., Xu, K.F., Fan, Q., Pacheco-Rodriguez, G., Moss, J., Vaughan, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. A novel splice variant of the cell adhesion molecule contactin 4 ( CNTN4) is mainly expressed in human brain. Zeng, L., Zhang, C., Xu, J., Ye, X., Wu, Q., Dai, J., Ji, C., Gu, S., Xie, Y., Mao, Y. J. Hum. Genet. (2002) [Pubmed]
  9. BIG1 and BIG2, brefeldin A-inhibited guanine nucleotide-exchange factors for ADP-ribosylation factors. Jones, H.D., Moss, J., Vaughan, M. Meth. Enzymol. (2005) [Pubmed]
  10. Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2). Li, H., Adamik, R., Pacheco-Rodriguez, G., Moss, J., Vaughan, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  11. Interaction of FK506-binding protein 13 with brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1): effects of FK506. Padilla, P.I., Chang, M.J., Pacheco-Rodriguez, G., Adamik, R., Moss, J., Vaughan, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  12. BIG2, a guanine nucleotide exchange factor for ADP-ribosylation factors: its localization to recycling endosomes and implication in the endosome integrity. Shin, H.W., Morinaga, N., Noda, M., Nakayama, K. Mol. Biol. Cell (2004) [Pubmed]
  13. The Brefeldin A-inhibited Guanine Nucleotide-exchange Protein, BIG2, Regulates the Constitutive Release of TNFR1 Exosome-like Vesicles. Islam, A., Shen, X., Hiroi, T., Moss, J., Vaughan, M., Levine, S.J. J. Biol. Chem. (2007) [Pubmed]
  14. The contactin 4 gene locus at 3p26 is a candidate gene of SCA16. Miura, S., Shibata, H., Furuya, H., Ohyagi, Y., Osoegawa, M., Miyoshi, Y., Matsunaga, H., Shibata, A., Matsumoto, N., Iwaki, A., Taniwaki, T., Kikuchi, H., Kira, J., Fukumaki, Y. Neurology (2006) [Pubmed]
  15. Identification and localization of two brefeldin A-inhibited guanine nucleotide-exchange proteins for ADP-ribosylation factors in a macromolecular complex. Yamaji, R., Adamik, R., Takeda, K., Togawa, A., Pacheco-Rodriguez, G., Ferrans, V.J., Moss, J., Vaughan, M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  16. The brefeldin A-inhibited GDP/GTP exchange factor 2, a protein involved in vesicular trafficking, interacts with the beta subunits of the GABA receptors. Charych, E.I., Yu, W., Miralles, C.P., Serwanski, D.R., Li, X., Rubio, M., De Blas, A.L. J. Neurochem. (2004) [Pubmed]
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