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FRZB (frizzled-related protein)
Sarah Thysen, Rik Lories
Laboratory for Skeletal Development and Joint Disorders, Department of Development and Regeneration,
KU Leuven, Belgium (ST, RL)
Published in Atlas Database: June 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/FRZBID44457ch2q32.html
DOI: 10.4267/2042/48464
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
a molecular weight of 36 kDa. FRZB is a member of
the secreted frizzled related protein (SFRP) family, of
which five members (SFRP1 to SFRP5) are known
within the human genome. SFRPs fold into two
independent domains, the cysteine-rich domain (CRD)
and the Netrin-like domain (NTN). The CRD domain
shares sequence homology with the extracellular
portion of the WNT receptor Frizzled (Fz).
Therefore, the CRD domain is considered the WNT
binding domain.
The NTN domain contains six cysteine residues that
most likely form three disulfide bridges and NTN
domains with similar features are found in several
unrelated proteins, including Netrin-1, tissue inhibitors
of metallo-proteinases (TIMPs), complement proteins
and type I procollagen C-proteinase enhancer proteins
(PCOLCEs).
The overall function of the NTN domain is unknown.
However, one study demonstrated that both domains
are necessary for optimal WNT inhibition (Jones et al.,
2002; Bath et al., 2007).
Identity
Other names: FRE, FRITZ, FRP-3, FRP, FRZB-1,
FRZB-PEN, FRZB1, FZRB, OS1, SFRP3, hFIZ
HGNC (Hugo): FRZB
Location: 2q32.1
DNA/RNA
Description
Genomic size: 40762 bp, encoded by 6 exons.
Transcription
Transcript length: 3162 bp; mRNA: 978 bp.
Pseudogene
Human FRZB has only 1 known transcript.
Protein
Description
FRZB protein is comprised of 325 amino acids with
The FRZB gene (40762 bp) contains a total of 6 exons and the FRZB transcript is 978 bp.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1)
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FRZB (frizzled-related protein)
Thysen S, Lories R
Structure of FRZB. FRZB contains a cysteine-rich domain (CRD) and a Netrin-like (NTN) domain. It is hypothesised that the
antagonistic effects of FRZB can be explained by the binding of WNTs to the CRD domain.
were found to be associated to knee, hip, generalized
and radiographic osteoarthritis (Loughlin et al., 2004;
Min et al., 2005; Lories et al., 2005; Lane et al., 2006;
Valdes et al., 2007). However, the results from a recent
meta-analysis showing no overall effect of FRZB
genetic variants on hip or knee OA debated this
association (Evangelou et al., 2009).
Expression
SFRP3 (FRZB) was originally isolated from bovine
articular cartilage. During human embryonic and fetal
development FRZB is primarily expressed in
cartilaginous cores of developing long bones (Hoang et
al., 1996). In the early mouse embryo, mFrzb-1 is
expressed in the primitive streak, presomitic mesoderm,
somites, and brain. Later, mFrzb-1 exhibits sharp
boundaries of expression in the limb bud, branchial
arches, facial mesenchyme, and in cartilaginous
elements of the appendicular skeleton (Hoang et al.,
1998).
Implicated in
Osteoarthritis
Note
Osteoarthritis is a chronic degenerative joint disease
without underlying autoimmune or autoinflammatory
mechanisms. The disease leads to pain and disability
and affects millions of people worldwide. Although
once considered as a disease of the articular cartilage,
the current concept holds that the whole joint is
involved, including the subchondral bone, menisci,
ligaments, periarticular muscle, capsule and synovium.
Osteoarthritis is a complex disorder to which both
genetic and acquired factors contribute (Hunter et al.,
2006).
Polymorphisms in FRZB (Arg200Trp and Arg324Gly)
have been associated with osteoarthritis (Loughlin et
al., 2004; Min et al., 2005; Lories et al., 2005; Lane et
al., 2006; Valdes et al., 2007).
However, the results from a recent meta-analysis
showing no overall effect of FRZB genetic variants on
hip or knee OA debated this association (Evangelou et
al., 2009).
Recently, a transcriptomics analysis in Frzb-/- mice
provided evidence for a tight regulation of WNT
signalling and highlighted the complex role for FRZB
in joint homeostasis (Lodewyckx et al., 2012).
Moreover, Frzb-/- mice show increased cartilage
damage when challenged by different models of acute
and short-term joint, suggesting a role for FRZB in
osteoarthritis. The observed cartilage damage was
associated with increased WNT signalling and matrix
metalloproteinase 3 (MMP-3) expression and activity.
Localisation
Extracellular space, bound to plasma membrane.
Function
FRZB is involved in the WNT/beta-catenin signalling
pathway by acting as an inhibitor by binding to WNT
ligands. However, recent studies indicate that SFRPs
can modulate WNT signalling and are able to interact
with molecules that are unrelated to the WNT
signalling cascades and among which there is no
apparent relationship (Bovolenta et al., 2008).
Homology
FRZB is a member of the secreted frizzled related
protein (SFRP) family (SFRP1-5). Based on their
amino acid sequence homology, they are divided into a
subgroup consisting of SFRP1, SFRP2 and SFRP5 and
a subgroup comprising SFRP3 (FRZB) and SFRP4.
SFRPs contain a CRD domain that shares sequence
homology with the extracellular portion of the WNT
receptor Frizzled (Fz) (Jones et al., 2005).
Mutations
Germinal
The only clinically associated variants of FRZB are
Arg200Trp (exon 4) and Arg324Gly (exon 6). Both of
them are substitutions for a conserved arginine residue.
One or two FRZB SNPs or a haplotype containing both
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1)
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FRZB (frizzled-related protein)
Thysen S, Lories R
Additionally, Frzb-/- mice have increased cortical bone
thickness and density without changes in the trabecular
bone (Lories et al., 2007).
Cytogenetics
The haplotype coding for substitutions of two highly
conserved arginine residues (Arg200Trp and
Arg324Gly) in FRZB are associated with hip
osteoarthritis in females. Moreover, transfection studies
indicated that substitutions of these positively charged
residues reduced the ability of FRZB to inhibit WNT
signalling (Loughlin et al., 2004). Additionally, an
association analysis confirmed that the R324G variant
of the FRZB gene is involved in osteoarthritis and
indicates a role of this variant in several generalized
OA phenotypes (Min et al., 2005). Next, evidence was
found for a differential association of the FRZB
Arg200Trp polymorphism with hip osteoarthritis and
osteoporosis (Lories et al., 2005). Lane et al. confirmed
the earlier finding that a rare haplotype with both
Arg200Trp and Arg324Gly FRZB variants contributes
to hip osteoarthritis in women. Further, an association
of genetic polymorphisms of FRZB and knee
osteoarthritis was found (Valdes et al., 2007). In
contrast, Rodriguez-Lopez et al. could not find an
association of FRZB polymorphisms with either
generalised osteoarthritis or hip OA. But, their results
suggest that the Arg324Gly SNP may have an effect in
the development of osteoarthritis in multiple joints.
Furthermore, a large-scale meta-analysis of individuallevel data does not support the association of SNPs of
FRZB with osteoarthritis (Evangelou et al., 2009).
Osteogenic sarcoma
Note
Micro-array analysis shows that FRZB has virtually no
mRNA expression in osteogenic sarcoma-derived
specimens compared to control (Mandal et al., 2007).
Breast cancer
Note
Expression of FRZB is turned off in breast carcinomas
(versus normal breasts). These results suggest that
FRZB is a candidate gene for malignancies (Ugolini et
al., 1999).
Renal cancer
Note
A kidney tissue microarray and analysis of FRZB
overexpression in a renal cancer cell line shows that
sFRP3 expression promotes cell growth, invasion, and
inhibition of apoptosis in renal cancer cells (Hirata et
al., 2010).
Bladder cancer
Note
Methylation of HOXB2, KRT13 and FRZB are
associated with aggressive invasive bladder cancer
(Marsit et al., 2010).
Malignant pleural mesothelioma
Note
The transcription of the SFRP family is frequently
down-regulated in human malignant pleural
mesothelioma (Lee et al., 2004).
Colorectal cancer
Soft tissue sarcomas
Note
The functional genetic variant Arg324Gly of FRZB
was shown to be associated with colorectal cancer risk
(Shanmugam et al., 2007). However, Berndt et al.
observed no association for either polymorphisms
(Arg324Gly and Arg200Trp) or any haplotypes with
colorectal adenoma or colorectal cancer.
Note
FRZB overexpression in fibrosarcoma and liposarcoma
cell lines reduces cell motility, invasiveness and
tumorigenesis.
These results implicate an important tumor suppressive
function for FRZB in sarcomas (Guo et al., 2008).
Melanoma
Gastric cancer
Note
FRZB expression is reduced in malignant melanoma
tissues and cell lines compared to normal cells and this
down-regulation is related to methylation of the FRZB
gene.
Additionally, recombinant FRZB decreases migration
and invasion of melanoma cells (Ekström et al., 2011).
Note
Overexpression of FRZB in gastric cancer cell
suppresses proliferation and modulates the balance
between proliferation and differentiation in gastric
cancer (Qu et al., 2008c). Additionally, FRZB exhibits
anti-tumor ability in gastric cancer cell line SGC-7901
in vitro and in vivo, and decreases the expression of
MMP-2, MMP-7 and MMP-9 leading to a reduced
invasion ability of the tumor cells (Qu et al., 2008b).
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Prostate cancer
Note
Ectopic expression of FRZB in an androgenindependent prostate cancer cellular model results in
the suppression of tumor growth and cellular
invasiveness. This provides evidence that FRZB can act
as a tumor suppressor gene (Zi et al., 2005).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1)
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FRZB (frizzled-related protein)
Thysen S, Lories R
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This article should be referenced as such:
Valdes AM, Loughlin J, Oene MV, Chapman K, Surdulescu
GL, Doherty M, Spector TD. Sex and ethnic differences in the
association of ASPN, CALM1, COL2A1, COMP, and FRZB
with genetic susceptibility to osteoarthritis of the knee. Arthritis
Rheum. 2007 Jan;56(1):137-46
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1)
Thysen S, Lories R. FRZB (frizzled-related protein). Atlas
Genet Cytogenet Oncol Haematol. 2013; 17(1):8-11.
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