Alternative titles; symbols
HGNC Approved Gene Symbol: CCN2
Cytogenetic location: 6q23.2 Genomic coordinates (GRCh38): 6:131,948,176-131,951,372 (from NCBI)
Bradham et al. (1991) described a novel mitogen produced by human umbilical vein endothelial cells that they termed connective tissue growth factor. The protein, related to platelet-derived growth factor (see 190040), was predicted from its cDNA to be a 349-amino acid, 38-kD cysteine-rich secreted protein.
Martinerie et al. (1992) identified a locus sharing homology with the nov protooncogene overexpressed in avian nephroblastoma and corresponding to the CTGF gene.
By analysis of Northern blots, Kim et al. (1997) found that CTGF is expressed as a 2.4-kb mRNA in a broad spectrum of human tissues. Sequence comparison revealed that CTGF belongs to a group known as the immediate-early genes, which are expressed after induction by growth factors or certain oncogenes (see 164958). The immediate-early genes have significant sequence homology to the insulin-like growth factor-binding proteins (IGFBPs) and contain the conserved N-terminal IGFBP motif (see IGFBP7, 602867). CTGF shares 28 to 38% amino acid identity with IGFBPs 1-6.
Kim et al. (1997) demonstrated that CTGF specifically bound insulin-like growth factors (IGFs), although with relatively low affinity. They proposed that the immediate-early genes, together with IGFBP7, constitute a subfamily of IGFBP genes whose products bind IGFs with low affinity.
Mokalled et al. (2016) performed a genomewide profiling screen for secreted factors that are upregulated during zebrafish spinal cord regeneration and found that connective tissue growth factor a (ctgfa) is induced in and around glial cells that participate in initial bridging events. Mutations in ctgfa disrupted spinal cord repair, and transgenic ctgfa overexpression or local delivery of human CTGF recombinant protein accelerated bridging and functional regeneration. Mokalled et al. (2016) concluded that their study revealed that CTGF is necessary and sufficient to stimulate glial bridging and natural spinal cord regeneration.
Martinerie et al. (1992) assigned the CTGF gene to chromosome 6q23.1 by a combination of study of mouse/human somatic cell hybrids and fluorescence in situ hybridization. They showed that CTGF is situated proximal to MYB (189990).
Fonseca et al. (2007) genotyped a polymorphism in the promoter of the CTGF gene, G-945C (rs6918698), in 1,000 subjects in 2 groups: group 1 consisted of 200 patients with systemic sclerosis (181750) and 188 control subjects; group 2 consisted of 300 patients with systemic sclerosis and 312 control subjects. The combined groups represented an estimated 10% of patients with systemic sclerosis in the United Kingdom. The GG genotype was significantly more common in patients with systemic sclerosis than in control subjects in both groups, with an odds ratio for the combined group of 2.2 (95% confidence interval, 1.5 to 3.2; P less than 0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of antitopoisomerase I antibodies (odds ratio, 3.3; 95% confidence interval, 2.0 to 5.6; P less than 0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% confidence interval, 1.9 to 5.0; P less than 0.001). Fonseca et al. (2007) observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo. Fonseca et al. (2007) concluded that the G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis.
Hepatointestinal schistosomiasis is caused by 2 species of helminths: Schistosoma japonicum, which is prevalent in Asia, and S. mansoni, which is prevalent in Africa and South America. Development of hepatic fibrosis occurs in 5 to 10% of schistosome-infected individuals and is influenced by a locus on chromosome 6q23 (SM2; 604201) containing the IFNGR1 (107470) and CTGF genes. Dessein et al. (2009) found that the SNP rs9402373, which lies close to the CTGF gene, was associated with severe hepatic fibrosis in Chinese fisherman and farmers infected with S. japonicum and in Sudanese and Brazilian patients infected with S. mansoni (P = 2 x 10(-6); OR = 2.01). Another SNP, rs1256196, which is also in close proximity to CTGF, was associated independently with severe fibrosis in the Chinese and Sudanese individuals (P = 6 x 10(-4); OR = 1.94). Metaanalysis of the SNPs determined that the CC genotype of rs9402373 and the TT genotype of rs1256196 were associated with disease. In silico analysis and EMSA experiments showed that the SNPs affected nuclear factor binding, suggesting that they may alter gene transcription or transcript stability. Dessein et al. (2009) proposed that rs9402373 and rs1256196 may be markers for the prediction of disease progression and identify critical steps in the development of hepatic fibrosis.
For discussion of a possible association between variation in the CTGF gene and diabetic nephropathy, see MVCD1 (603933).
Nakanishi et al. (2001) generated transgenic mice that overexpressed CTGF under the control of the mouse type XI collagen (see 120280) promoter. Embryonic and neonatal growth occurred normally, but transgenic mice showed dwarfism within a few months after birth. X-ray analysis revealed that their bone density was decreased compared with that of normal mice. Nakanishi et al. (2001) concluded that overexpression of CTGF affects certain steps of endochondral ossification. In addition, the testes were much smaller than normal and fertility was affected in transgenic mice, indicating that CTGF may also regulate the embryonic development of the testis.
Ercan et al. (2017) found that loss of Tsc1 (605284)/Tsc2 (191092) in mouse neurons resulted in a block in oligodendrocyte development in vitro and in oligodendrocyte hypomyelination in vivo. These processes were mediated by neuronal Ctgf, which was highly expressed and secreted from Tsc-deficient neurons and blocked development of oligodendrocytes. Expression of Srf (600589), the transcriptional regulator of Ctgf, was also decreased in Tsc-deficient neurons. Myelination could be improved by genetic ablation of Ctgf in neurons lacking Tsc1. Electron microscopy analysis suggested that this rescue of myelination was caused by the rescue of myelinated axon numbers, rather than changes in myelin thickness.
Bradham, D. M., Igarashi, A., Potter, R. L., Grotendorst, G. R. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J. Cell Biol. 114: 1285-1294, 1991. [PubMed: 1654338] [Full Text: https://doi.org/10.1083/jcb.114.6.1285]
Dessein, A., Chevillard, C., Arnaud, V., Hou, X., Hamdoun, A. A., Dessein, H., He, H., Abdelmaboud, S. A., Luo, X., Li, J., Varoquaux, A., Mergani, A., and 12 others. Variants of CTGF are associated with hepatic fibrosis in Chinese, Sudanese, and Brazilians infected with Schistosomes. J. Exp. Med. 206: 2321-2328, 2009. [PubMed: 19822645] [Full Text: https://doi.org/10.1084/jem.20090383]
Ercan, E., Han, J. M., Di Nardo, A., Winden, K., Han, M.-J., Hoyo, L., Saffari, A., Leask, A., Geschwind, D. H., Sahin, M. Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex. J. Exp. Med. 214: 681-697, 2017. [PubMed: 28183733] [Full Text: https://doi.org/10.1084/jem.20160446]
Fonseca, C., Lindahl, G. E., Ponticos, M., Sestini, P., Renzoni, E. A., Holmes, A. M., Spagnolo, P., Pantelidis, P., Leoni, P., McHugh, N., Stock, C. J., Shi-Wen, X., Denton, C. P., Black, C. M., Welsh, K. I., du Bois, R. M., Abraham, D. J. A polymorphism in the CTGF promoter region associated with systemic sclerosis. New Eng. J. Med. 357: 1210-1220, 2007. [PubMed: 17881752] [Full Text: https://doi.org/10.1056/NEJMoa067655]
Kim, H.-S., Nagalla, S. R., Oh, Y., Wilson, E., Roberts, C. T., Jr., Rosenfeld, R. G. Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc. Nat. Acad. Sci. 94: 12981-12986, 1997. [PubMed: 9371786] [Full Text: https://doi.org/10.1073/pnas.94.24.12981]
Martinerie, C., Viegas-Pequignot, E., Guenard, I., Dutrillaux, B., Nguyen, V. C., Bernheim, A., Perbal, B. Physical mapping of human loci homologous to the chicken nov proto-oncogene. Oncogene 7: 2529-2534, 1992. [PubMed: 1334251]
Mokalled, M. H., Patra, C., Dickson, A. L., Endo, T., Stainier, D. Y. R., Poss, K. D. Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish. Science 354: 630-634, 2016. [PubMed: 27811277] [Full Text: https://doi.org/10.1126/science.aaf2679]
Nakanishi, T., Yamaai, T., Asano, M., Nawachi, K., Suzuki, M., Sugimoto, T., Takigawa, M. Overexpression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 decreases bone density in adult mice and induces dwarfism. Biochem. Biophys. Res. Commun. 281: 678-681, 2001. [PubMed: 11237711] [Full Text: https://doi.org/10.1006/bbrc.2001.4379]