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

• 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 [5].

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

• Northern blot analysis showed highest CNTN4 expression in testes, thyroid, small intestine, uterus and brain [1].
• Binding of BIG1, BIG2, and ARF to membranes was also increased by L-732,531, an agonist structurally related to FK506, but was not increased by a related antagonist, L-685,818, nor by cyclosporin A or rapamycin [11].
• Binding of BIG1, BIG2, and ARF to cell membranes in vitro was increased by guanosine 5'-[gamma-thio]triphosphate, and further increases were induced by FK506 [11].
• These observations together indicate that BIG2 is implicated in the structural integrity of the recycling endosome through activating class I ARFs [12].
• We investigated whether the brefeldin A (BFA)-inhibited guanine nucleotide-exchange proteins, BIG1 and/or BIG2, are required for TNFR1 release from human umbilical vein endothelial cells [13].

Associations of CNTN4 with chemical compounds

• BIG2, a guanine nucleotide exchange factor for ADP-ribosylation factors: its localization to recycling endosomes and implication in the endosome integrity [12].
• The Brefeldin A-inhibited Guanine Nucleotide-exchange Protein, BIG2, Regulates the Constitutive Release of TNFR1 Exosome-like Vesicles [13].

Other interactions of CNTN4

• Cloning and characterization of the human neural cell adhesion molecule, CNTN4 (alias BIG-2) [1].
• The contactin 4 gene locus at 3p26 is a candidate gene of SCA16 [14].
• CONCLUSION: The contactin 4 gene (CNTN4) is associated with cerebellar degeneration in spinocerebellar ataxia type 16 [14].

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].

References