Alternative titles; symbols
HGNC Approved Gene Symbol: FRZB
Cytogenetic location: 2q32.1 Genomic coordinates (GRCh38): 2:182,833,275-182,866,637 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.1 | {Osteoarthritis susceptibility 1} | 165720 | Multifactorial | 3 |
Transplantation experiments by Spemann and Mangold (1924) established the presence of an anatomically discrete region, the Spemann organizer, or dorsal lip, that controls patterning of the developing body axis in vertebrate embryos. Diffusible factors emanating from this region, such as 'goosecoid' (GSC; 138890) and 'noggin' (NOG; 602991), regulate skeletal morphogenesis. Drosophila cuticle hairs are arranged in a defined polarity that is genetically controlled by 'frizzled' (see FZD1; 603408), a 7-transmembrane receptor with a large extracellular cysteine-rich domain (CRD).
By RT-PCR and by screening bovine articular cartilage and human placenta cDNA libraries, Hoang et al. (1996) identified cDNAs encoding FRZB. The deduced 325-amino acid bovine and human FRZB proteins share 94% amino acid identity. Sequence analysis predicted that FRZB contains a 25-amino acid signal peptide, an N-terminal N-glycosylation site, a 24-amino acid putative transmembrane segment, a region with multiple potential ser/thr phosphorylation sites, and a serine-rich C-terminal domain. The N-terminal region of FRZB shares 50% amino acid identity, including the conservation of 10 cys residues, with the Drosophila frizzled protein. Immunoblot analysis determined that FRZB is expressed as an approximately 36-kD protein. In situ hybridization analysis of human embryos representing different stages of development detected no expression from week 6 through week 13 except in the developing appendicular skeleton, as well as in several craniofacial bones and epiphyseal ends of the rib cage. Immunochemical analysis confirmed the expression of FRZB in the developing skeletal structures.
During a differential screen for cDNAs enriched in the Spemann organizer, Leyns et al. (1997) isolated a cDNA encoding Xenopus Frzb. They isolated a mouse Frzb cDNA by screening an embryo cDNA library, and by searching an EST database for sequences similar to mouse Frzb, they identified overlapping ESTs encoding human FRZB, which they called FRZB1. Northern blot analysis revealed that FRZB is expressed strongly in placenta and heart, at intermediate levels in brain, skeletal muscle, kidney, and pancreas, and at low levels in lung and liver. SDS-PAGE analysis detected secretion of FRZB, possibly after proteolytic cleavage, consistent with FRZB's lack of the 7 transmembrane domains found in the Drosophila and vertebrate frizzled gene family. Functional analysis in Xenopus embryos showed that FRZB can antagonize the early and late effects of WNT8 (see 601396) signaling in the extracellular space after secretion of both proteins. Mammalian WNT genes, homologs of the Drosophila 'wingless' gene, are oncogenes that lead to mammary tumors.
Rattner et al. (1997) cloned FRZB, which they termed SFRP3. Transfection of membrane-anchored derivatives of SFRP3 and SFRP2 (604157) into embryonic kidney cells led to cell-surface binding of the Drosophila wingless protein.
By RT-PCR analysis, Schumann et al. (2000) showed that expression of SFRP1 (604156), SFRP2, and FZD2 (600667) was unchanged in failing myocardium compared with nonfailing controls, whereas expression of SFRP3 and SFRP4 (606570) was elevated. In situ RT-PCR analysis detected expression of SFRP3 and SFRP4 in cardiomyocytes. Western blot analysis indicated that beta-catenin (CTNNB1; 116806) expression was decreased in myocardium with high SFRP3 and SFRP4 levels. Schumann et al. (2000) proposed that paracrine WNT/frizzled signaling is inhibited by SFRPs in overloaded myocardium and that this inhibition is associated with depletion of cytosolic CTNNB1 and the induction of apoptosis susceptibility.
Dann et al. (2001) determined the crystal structures of the CRDs from mouse Fzd8 (606146) and FRZB after eliminating their N-linked glycosylation sites by mutation. The CRD structures were predominantly alpha helical, with all cysteines forming disulfide bonds. They appeared to represent a novel fold distantly related to 4-helix bundles. Using 3 mutagenesis strategies, Dann et al. (2001) implicated a single region on the CRD surface as important for WNT binding.
By searching an STS database, Leyns et al. (1997) mapped the FRZB gene to 2q31-q33. They noted that loss of 1 copy of the 2q arm occurs with high incidence in lung and colorectal carcinomas, as well as in neuroblastomas, and suggested that FRZB might function as a tumor suppressor gene.
Osteoarthritis Susceptibility
Osteoarthritis (OA; 165720) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Slagboom et al. (2000) and Loughlin et al. (2002) found evidence for linkage of hip osteoarthritis to chromosome 2q. In the report of Loughlin et al. (2002), the linkage centered at marker D2S2284 on chromosome 2q31.1, which had a maximum multipoint lod score of 1.6 in 378 affected sib pair families. Loughlin et al. (2004) used microsatellite targeting of 8 candidate genes in the 2q23-q32 region with known roles in skeletal development or homeostasis to demonstrate significant associations with the tumor necrosis factor-alpha-induced protein-6 gene (TNFAIP6; 600410) in all probands and the integrin alpha-6 (ITGA6; 147556) and FRZB genes in female probands. However, genotyping showed lack of association for a nonsynonymous SNP in TNFAIP6, whereas a SNP in FRZB resulting in an arg324-to-gly substitution (R324G; 605083.0001) at the C terminus was associated with hip osteoarthritis in the female probands (p = 0.04). The association was confirmed in an independent cohort of female hip cases. In addition, a haplotype coding for substitutions of 2 highly conserved arginine residues in FRZB, R324G and arg200 to trp (R200W; 605083.0002), was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (p = 0.004). The FRZB protein is a soluble antagonist of WNT signaling. Variant secreted FRZB with the R324G substitution was found to have diminished ability to antagonize WNT signaling in vitro. Loughlin et al. (2004) concluded that functional polymorphisms within FRZB conferred susceptibility for hip OA in females and implicated the WNT signaling pathway in the pathogenesis of this disease.
Role in Atrioventricular Septal Defect
Ackerman et al. (2012) used a candidate gene approach among individuals with Down syndrome and complete atrioventricular septal defect (AVSD) (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but in fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (120220), COL6A2 (120240), CRELD1 (607170) (already identified as a cause of AVSD; see 606217), FBLN2 (135821), FRZB, and GATA5 (611496). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans.
By linkage and association studies, Loughlin et al. (2004) found that an arg324-to-gly (R324G) (rs7775) substitution in the FRZB gene was associated with osteoarthritis of the hip in females (see OS1, 165720). The association was confirmed in an independent cohort of female hip cases (p = 0.04).
By linkage and association studies, Loughlin et al. (2004) identified a haplotype in the FRZB gene, defined by arg200-to-trp (R200W; 605083.0001) and arg324-to-gly (R324G) (rs288326) substitutions, as a strong risk factor for primary osteoarthritis of the hip in females (see OS1, 165720) (OR = 4.1, p = 0.004).
Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects. Am. J. Hum. Genet. 91: 646-659, 2012. [PubMed: 23040494] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.017]
Dann, C. E., Hsieh, J.-C., Rattner, A., Sharma, D., Nathans, J., Leahy, D. J. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412: 86-90, 2001. [PubMed: 11452312] [Full Text: https://doi.org/10.1038/35083601]
Hoang, B., Moos, M., Jr., Vukicevic, S., Luyten, F. P. Primary structure and tissue distribution of FRZB, a novel protein related to Drosophila frizzled, suggest a role in skeletal morphogenesis. J. Biol. Chem. 271: 26131-26137, 1996. [PubMed: 8824257] [Full Text: https://doi.org/10.1074/jbc.271.42.26131]
Leyns, L., Bouwmeester, T., Kim, S.-H., Piccolo, S., De Robertis, E. M. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer. Cell 88: 747-756, 1997. [PubMed: 9118218] [Full Text: https://doi.org/10.1016/s0092-8674(00)81921-2]
Loughlin, J., Dowling, B., Chapman, K., Marcelline, L., Mustafa, Z., Southam, L., Ferreira, A., Ciesielski, C., Carson, D. A., Corr, M. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc. Nat. Acad. Sci. 101: 9757-9762, 2004. [PubMed: 15210948] [Full Text: https://doi.org/10.1073/pnas.0403456101]
Loughlin, J., Dowling, B., Mustafa, Z., Southam, L., Chapman, K. Refined linkage mapping of a hip osteoarthritis susceptibility locus on chromosome 2q. (Letter) Rheumatology 41: 955-956, 2002. [PubMed: 12154223] [Full Text: https://doi.org/10.1093/rheumatology/41.8.955]
Rattner, A., Hsieh, J.-C., Smallwood, P. M., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc. Nat. Acad. Sci. 94: 2859-2863, 1997. [PubMed: 9096311] [Full Text: https://doi.org/10.1073/pnas.94.7.2859]
Schumann, H., Holtz, J., Zerkowski, H.-R., Hatzfeld, M. Expression of secreted frizzled related proteins 3 and 4 in human ventricular myocardium correlates with apoptosis related gene expression. Cardiovasc. Res. 45: 720-728, 2000. [PubMed: 10728394] [Full Text: https://doi.org/10.1016/s0008-6363(99)00376-4]
Slagboom, P. E., Heijmans, B. T., Beekman, M., Westendorp, R. G. J., Meulenbelt, I. Genetics of human aging: the search for genes contributing to human longevity and diseases of the old. Ann. New York Acad. Sci. 908: 50-63, 2000. [PubMed: 10911947] [Full Text: https://doi.org/10.1111/j.1749-6632.2000.tb06635.x]
Spemann, H., Mangold, H. Ueber induktion von embryonalanlagen durch implantation artfremder organisatoren. Arch. Mikroskopische Anat. Entwicklungsmechanik 100: 599-638, 1924.