Alternative titles; symbols
HGNC Approved Gene Symbol: CCN6
Cytogenetic location: 6q21 Genomic coordinates (GRCh38) : 6:112,052,813-112,069,686 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q21 | Progressive pseudorheumatoid dysplasia | 208230 | Autosomal recessive | 3 |
Pennica et al. (1998) cloned and characterized 3 genes downstream in the Wnt signaling pathway that are relevant to malignant transformation: WISP1 (603398), WISP2 (603399), and WISP3. The WISP3 cDNA encodes a 354-amino acid protein. The authors found that WISP1 and WISP3 were overexpressed in colon tumors, whereas WISP2 expression was reduced.
Using small interfering RNA, Miller and Sen (2007) showed that reduced WISP3 expression in a human chondrocyte cell line increased the amount of cellular reactive oxygen species (ROS). Conversely, treatment of chondrocytes or human umbilical vein endothelial cells with soluble WISP3 reduced ROS levels. Two disease-associated mutations in WISP3, cys78 to arg (C78R; 603400.0004) and trp331 to ter (W331X; 603400.0002), were associated with high cellular ROS levels. Miller and Sen (2007) concluded that WISP3 regulates accumulation of cellular ROS.
Nakamura et al. (2007) found that overexpression of Wisp3 inhibited BMP (see 112264) and WNT (see 164820) signaling during zebrafish development. Zebrafish and human WISP3 inhibited BMP and WNT signaling in mammalian cells by binding to BMPs and to the WNT coreceptors LRP6 (603507) and frizzled (see 603408), respectively. WISP3 with progressive pseudorheumatoid dysplasia (PPD; 208230)-causing mutations had reduced activity in these assays. Morpholino-mediated inhibition of Wisp3 expression in developing zebrafish affected pharyngeal cartilage size and shape. Nakamura et al. (2007) concluded that dysregulation of BMP and/or WNT signaling contributes to cartilage failure in humans with PPD.
By use of a radiation hybrid mapping panel, Pennica et al. (1998) mapped the WISP3 gene to 6q22-q23, approximately 18 Mb proximal to connective tissue growth factor (CTGF; 121009) at 6q23.1 and 23 Mb proximal to MYB (189990) at 6q22.
WISP3 is a member of the CCN (for CTGF, CYR61 (602369), and NOV (164958)) gene family, which encode cysteine-rich secreted proteins with roles in cell growth and differentiation (Bork, 1993). Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest that they have nonredundant roles. Using a positional-candidate approach, Hurvitz et al. (1999) found that mutations in the WISP3 gene are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid arthropathy (PPRD; 208230). Patients with this disorder are asymptomatic in early childhood. Signs and symptoms of disease typically develop between 3 and 8 years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations had not been reported in this disorder. Cartilage appears to be the primary affected tissue, and in 1 patient studied by Spranger et al. (1983), a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones. Hurvitz et al. (1999) identified 9 different mutations in the WISP3 gene in unrelated affected individuals, indicating that the gene is essential for normal postnatal skeletal growth and cartilage homeostasis. Of the 9 mutations found, those in patients from Italy, France, and the U.S. were present in compound heterozygous state; those from Saudi Arabia, Jordan, and Iran were present in homozygous state, reflecting the differences in the frequency of consanguinity in the different populations.
In an Italian family with progressive pseudorheumatoid arthropathy (PPRD; 208230), Hurvitz et al. (1999) found compound heterozygosity for a G-to-A transition at nucleotide 434 of the WISP3 gene, resulting in a cys145-to-tyr (C145Y) substitution, and a G-to-A transition at nucleotide 993 of the WISP3 gene, resulting in a trp331-to-ter substitution (W331X; 603400.0002).
For discussion of the trp331-to-ter (W331X) mutation in the WISP3 gene that was found in compound heterozygous state in a family with progressive pseudorheumatoid arthropathy (PPRD; 208230) by Hurvitz et al. (1999), see 603400.0001.
In a French family with progressive pseudorheumatoid arthropathy (PPRD; 208230), Hurvitz et al. (1999) found compound heterozygosity for a C-to-A transversion at nucleotide 156 of the CCN6 gene, resulting in a cys52-to-ter (C52X) substitution, and a T-to-C transition at nucleotide 232 of the WISP3 gene, resulting in a cys78-to-arg substitution (C78R; 603400.0004).
For discussion of the cys78-to-arg (C78R) mutation in the WISP3 gene that was found in compound heterozygous state in a family with progressive pseudorheumatoid arthropathy (PPRD; 208230) by Hurvitz et al. (1999), see 603400.0003.
In 2 families from Saudi Arabia and 1 family from Jordan with progressive pseudorheumatoid arthropathy (PPRD; 208230), Hurvitz et al. (1999) found homozygosity for a 1-bp deletion at nucleotide 246 of the WISP3 gene, resulting in a frameshift after residue 82 with a stop 21 residues downstream.
In a family from Jordan with progressive pseudorheumatoid arthropathy (PPRD; 208230), Hurvitz et al. (1999) found homozygosity for an altered intron 1 splice donor site, an insertion of a T at the second nucleotide.
In a family from the United States with progressive pseudorheumatoid arthropathy (PPRD; 208230), Hurvitz et al. (1999) found compound heterozygous mutations in the WISP3 gene: a 2-bp insertion at nucleotide 863, resulting in a frameshift at residue 288 with a stop 24 residues downstream, and 2-bp deletion at nucleotide 43 (43_44delGC; 603400.0008), resulting in a frameshift at residue 15 with a stop 15 residues downstream.
For discussion of the 2-bp deletion (43_44delGC)in the WISP3 gene that was found in compound heterozygous state in a family with progressive pseudorheumatoid arthropathy (PPRD; 208230) by Hurvitz et al. (1999), see 603400.0007.
In a family from Iran with progressive pseudorheumatoid arthropathy (PPRD; 208230), Hurvitz et al. (1999) found homozygosity for a 2-bp deletion at nucleotide 866 of the WISP3 gene, resulting in a frameshift at residue 289 with a stop 11 residues downstream.
In affected members of a Chinese family with progressive pseudorheumatoid arthropathy (PPRD; 208230), Liao et al. (2004) identified a T-to-C transition in the WISP3 gene, changing codon 334 from TCT (ser) to CCT (pro) (S334P).
In affected members of a Chinese family with progressive pseudorheumatoid arthropathy (PPRD; 208230), Liao et al. (2004) identified a 1-bp deletion (855delT) in the WISP3 gene, resulting in a frameshift.
Bork, P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett. 327: 125-130, 1993. [PubMed: 7687569] [Full Text: https://doi.org/10.1016/0014-5793(93)80155-n]
Hurvitz, J. R., Suwairi, W. M., Van Hul, W., El-Shanti, H., Superti-Furga, A., Roudier, J., Holderbaum, D., Pauli, R. M., Herd, J. K., Van Hul, E., Rezai-Delui, H., Legius, E., Le Merrer, M., Al-Alami, J., Bahabri, S. A., Warman, M. L. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nature Genet. 23: 94-98, 1999. [PubMed: 10471507] [Full Text: https://doi.org/10.1038/12699]
Liao, E. Y., Peng, Y. Q., Zhou, H. D., Mackie, E. J., Li, J., Hu, P. A., Zhou, S. H., Wen, G. B., Zhai, M. X., Luo, X. H., Tan, L. H., Ni, J. D. Human gene mutations. Hum. Genet. 115: 169 only, 2004. [PubMed: 15300964]
Liao, E. Y., Peng, Y. Q., Zhou, H. D., Mackie, E. J., Li, J., Hu, P. A., Zhou, S. H., Wen, G. B., Zhai, M. X., Luo, X. H., Tan, L. H., Ni, J. D. Human gene mutations. Hum. Genet. 115: 174 only, 2004. [PubMed: 15300987]
Miller, D. S., Sen, M. Potential role of WISP3 (CCN6) in regulating the accumulation of reactive oxygen species. Biochem. Biophys. Res. Commun. 355: 156-161, 2007. [PubMed: 17286957] [Full Text: https://doi.org/10.1016/j.bbrc.2007.01.114]
Nakamura, Y., Weidinger, G., Liang, J. O., Aquilina-Beck, A., Tamai, K., Moon, R. T., Warman, M. L. The CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signaling. J. Clin. Invest. 117: 3075-3086, 2007. [PubMed: 17823661] [Full Text: https://doi.org/10.1172/JCI32001]
Pennica, D., Swanson, T. A., Welsh, J. W., Roy, M. A., Lawrence, D. A., Lee, J., Brush, J., Taneyhill, L. A., Deuel, B., Lew, M., Watanabe, C., Cohen, R. L., Melhem, M. F., Finley, G. G., Quirke, P., Goddard, A. D., Hillan, K. J., Gurney, A. L., Botstein, D., Levine, A. J. WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc. Nat. Acad. Sci. 95: 14717-14722, 1998. [PubMed: 9843955] [Full Text: https://doi.org/10.1073/pnas.95.25.14717]
Spranger, J., Albert, C., Schilling, F., Bartsocas, C., Stoss, H. Progressive pseudorheumatoid arthritis of childhood (PPAC): a hereditary disorder simulating rheumatoid arthritis. Europ. J. Pediat. 140: 34-40, 1983. [PubMed: 6873109] [Full Text: https://doi.org/10.1007/BF00661902]