Alternative titles; symbols
HGNC Approved Gene Symbol: FZD2
SNOMEDCT: 725165009;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:44,557,484-44,561,262 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Omodysplasia 2 | 164745 | Autosomal dominant | 3 |
Following up on the identification of trinucleotide repeat expansions as the basis of many inherited human disorders, Zhao et al. (1995) isolated and characterized cDNAs containing trinucleotide repeats. In the course of these studies, they discovered a human homolog of the Drosophila polarity gene 'frizzled' (fz). The fz locus in Drosophila is required for the transmission of polarity signals across the plasma membrane in epidermal cells. The Drosophila fz gene encodes a protein with 7 putative transmembrane domains that is thought to function as a G protein-coupled receptor. Zhao et al. (1995) isolated a human homolog, symbolized FZD2, from a human ovarian cDNA library. The full-length cDNA of FZD2 encodes a protein of 565 amino acids that shares 56% sequence identity with the Drosophila fz protein. Zhao et al. (1995) found that the expression of the FZD2 gene appears to be developmentally regulated, with high levels of expression in fetal kidney and lung and in adult colon and ovary. The structure of FZD2 suggests that it has a role in transmembrane signal transmission, although its precise physiologic function and associated pathways have yet to be determined. Wang et al. (1996) showed that a large family of frizzled homologs exists in mammals. These authors also isolated another human homolog, 'frizzled-5' (FZD5; 601723).
By in situ hybridization for Fzd2 in chicken embryos, Saal et al. (2015) observed expression throughout the developing head and within the proximal limb mesenchyme. Fzd2 protein was detected in both the developing head and limb.
Zhao et al. (1995) mapped the FZD2 gene to chromosome 17q21.1 by fluorescence in situ hybridization.
Wang et al. (1996) mapped the mouse Fzd2 gene to chromosome 11, syntenic to human chromosome 17q, by interspecific backcross analysis.
Crystal Structure
Chen et al. (2018) presented the crystal structure of a C. difficile toxin B (TcdB) fragment in complex with the cysteine-rich domain of human FZD2 at 2.5-angstrom resolution, which revealed an endogenous FZD-bound fatty acid acting as a coreceptor for TcdB binding. This lipid occupies the binding site for Wnt-adducted palmitoleic acid in FZDs. TcdB binding locks the lipid in place, preventing Wnt from engaging FZDs and signaling.
The rat frizzled-2 receptor binds Wnt proteins and can signal by activating calcium release from intracellular stores. Ahumada et al. (2002) demonstrated that the wildtype Fzd2 and a chimeric receptor consisting of the extracellular and transmembrane portions of the beta-2-adrenergic receptor with cytoplasmic domains of Fzd2 also signaled through modulation of cGMP. Activation of either receptor led to a decline in the intracellular concentration of cGMP, a process that was inhibited in cells treated with pertussis toxin, reduced by suppression of the expression of the G protein transducin (GNAT2; 139340), and suppressed through inhibition of cGMP-specific phosphodiesterase (PDE) activity. Moreover, Ahumada et al. (2002) showed that PDE inhibitors blocked Fzd2-induced calcium transients in zebrafish embryos. Thus, Ahumada et al. (2002) concluded that FZD2 appears to couple to PDEs and calcium transients through G proteins.
Using CRISPR-Cas9-mediated genomewide screens, Tao et al. (2016) identified members of the FZD family as receptors for Clostridium difficile toxin B (TcdB). TcdB bound to the cys-rich domains (CRDs) of FZD proteins, with highest affinity for FZD1 (603408), FZD2, and FZD7 (603410). TcdB competed with Wnt for binding to FZDs, and binding of TcdB blocked Wnt signaling. HeLa cells lacking FZD1, FZD2, and FZD7 were highly resistant to TcdB. Recombinant FZD2-CRD prevented TcdB binding to colonic epithelium organoids and to colonic epithelium of mice. Colonic epithelium of mice lacking Fzd7 was less susceptible to TcdB-induced tissue damage than that of wildtype mice. Tao et al. (2016) concluded that FZDs are physiologically relevant receptors for TcdB in colonic epithelium.
By aCGH in a 2-year-old boy (patient 8) who was diagnosed prenatally with a left-sided anterior congenital diaphragmatic hernia (CDH) and a large omphalocele, Wat et al. (2011) identified a de novo 17.4-kb deletion that involved only the FZD2 gene. The deletion occurred between 2 Alu repeats. Sequencing of the child's other FZD2 allele revealed no changes. Other anomalies in the child included a perimembranous ventral septal defect, a patent foramen ovale versus an atrial septal defect, bilateral inguinal hernias, and left-sided cryptorchidism.
In a mother and daughter with omodysplasia (OMOD2; 164745), Saal et al. (2015) identified heterozygosity for a nonsense mutation in the FZD2 gene (W548X; 600667.0001) that was not found in the unaffected individuals or public variant databases. Functional analysis showed that the mutant protein had reduced ability to interact with downstream targets and, in contrast to wildtype FZD2, could not facilitate the cellular response to canonical WNT (see 164820) signaling.
In a mother and daughter with omodysplasia (OMOD2; 164745), Saal et al. (2015) identified heterozygosity for a c.1644G-A transition in the FZD2 gene, resulting in a trp548-to-ter (W548X) substitution at the periphery of the canonical DISHEVELLED (see DVL1, 601365) interaction domain. The mutation arose de novo in the mother, as it was not found in her unaffected parents; it was also not found in an in-house database, or in the NHLBI ESP6500 or 1000 Genomes Projects databases. Functional analysis in HEK293T cells showed a significant reduction in colocalization of DVL and FZD2 with the mutant compared to wildtype FZD2. In contrast to a 3-fold increase in WNT (see 164820) signaling with wildtype FZD2, the W548X mutant showed no observable increase in WNT activity over that of background levels.
Ahumada, A., Slusarski, D. C., Liu, X., Moon, R. T., Malbon, C. C., Wang, H. Signaling of rat frizzled-2 through phosphodiesterase and cyclic GMP. Science 298: 2006-2010, 2002. [PubMed: 12471263] [Full Text: https://doi.org/10.1126/science.1073776]
Chen, P., Tao, L., Wang, T., Zhang, J., He, A., Lam, K., Liu, Z., He, X., Perry, K., Dong, M., Jin, R. Structural basis for recognition of frizzled proteins by Clostridium difficile toxin B. Science 360: 664-669, 2018. [PubMed: 29748286] [Full Text: https://doi.org/10.1126/science.aar1999]
Saal, H. M., Prows, C. A., Guerreiro, I., Donlin, M., Knudson, L., Sund, K. L., Chang, C.-F., Brugmann, S. A., Stottmann, R. W. A mutation in FRIZZLED2 impairs Wnt signaling and causes autosomal dominant omodysplasia. Hum. Molec. Genet. 24: 3399-3409, 2015. [PubMed: 25759469] [Full Text: https://doi.org/10.1093/hmg/ddv088]
Tao, L., Zhang, J., Meraner, P., Tovaglieri, A., Wu, X., Gerhard, R., Zhang, X., Stallcup, W. B., Miao, J., He, X., Hurdle, J. G., Breault, D. T., Brass, A. L., Dong, M. Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538: 350-355, 2016. [PubMed: 27680706] [Full Text: https://doi.org/10.1038/nature19799]
Wang, Y., Macke, J. P., Abella, B. S., Andreasson, K., Worley, P., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J. Biol. Chem. 271: 4468-4476, 1996. [PubMed: 8626800] [Full Text: https://doi.org/10.1074/jbc.271.8.4468]
Wat, M. J., Veenma, D., Hogue, J., Holder, A. M., Yu, Z., Wat, J. J., Hanchard, N., Shchelochkov, O. A., Fernandes, C. J., Johnson, A., Lally, K. P., Slavotinek, A., Danhaive, O., Schaible, T., Cheung, S. W., Rauen, K. A., Tonk, V. S., Tibboel, D., de Klein, A., Scott, D. A. Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia. J. Med. Genet. 48: 299-307, 2011. [PubMed: 21525063] [Full Text: https://doi.org/10.1136/jmg.2011.089680]
Zhao, Z. Y., Lee, C. C., Baldini, A., Caskey, C. T. A human homologue of the Drosophila polarity gene frizzled has been identified and mapped to 17q21.1. Genomics 27: 370-373, 1995. [PubMed: 7558010] [Full Text: https://doi.org/10.1006/geno.1995.1060]