FZD4 (frizzled class receptor 4)

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FZD4 (frizzled class receptor 4)

Written	2017-11	Alessandro Beghini, Adriana Cassaro
		Department of Health Sciences, University of Milan, via A. Di Rudini', 8 20142, Milan (Italy); alessandro.beghini@unimi.it; adriana.cassaro87@gmail.com

Abstract

Fzd4 is a receptor for Wnt proteins, belonging to the frizzled receptors family. Its stimulation can activate both Wnt/β-catenin canonical and Wnt/Ca²⁺ non canonical pathways. This receptor plays an important role in the development processes, in particular in the retinal vascularization: it binds the Norrin ligand, a Wnt-unrelated growth factor, and activates β-catenin signalling pathway. Mutations of FZD4 gene are associated with Familial Exudative Vitreoretinopathy (FEVR). Recently dysregulation of FZD4 expression has been reported in different type of cancers, but FZD4 contribution in tumor pathogenesis and progression is still not entirely elucidated.

Keywords

Frizzled 4, WNT, Wnt/β-catenin signaling

(Note : for Links provided by Atlas : click)

Identity

Alias_names	EVR1
	frizzled (Drosophila) homolog 4
	exudative vitreoretinopathy 1
	frizzled homolog 4 (Drosophila)
	frizzled 4, seven transmembrane spanning receptor
	frizzled family receptor 4
Alias_symbol (synonym)	CD344
Other alias	Frizzled 4, Seven Transmembrane Spanning Receptor
	Frizzled (Drosophila) homology 4
	Frizzled homolog 4 (Drosophila)
	CD344 Antigen
	FEVR
	Fz-4
	FZD4
	Wnt receptor Frizzled -4
	hFz4
HGNC (Hugo)	FZD4
LocusID (NCBI)	8322
Atlas_Id	40655
Location	11q14.2 [Link to chromosome band 11q14]
Location_base_pair	Starts at 86945675 and ends at 86955398 bp from pter ( according to hg19-Feb_2009) [Mapping FZD4.png]

Fusion genes
(updated 2017)

Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA



	Figure 1: Schematic representation of FZD4 gene that contains a total of two exons and FZD4 transcript.

Description	DNA size: 9.71kb encoding two exons. This gene has one transcript (splice variant), 82 orthologues, 12 paralogues (www.emsable.org). Sagara et al., reported a splice variant of FZD4 gene which they called FZD4SA, it retains intronic sequence and encodes shorter isoform of only 125 aa. However, its expression is not supported by other experimental evidences.
Transcription	The FZD4 mRNA transcript is 7383 bp. FZD4-001 ENST00000531380.1: mRNA7383 bp, protein 537 aa.

Protein

Description	The gene FZD4 encodes a 537 aa protein with a molecular weight of 59 kDa. FZD4 is a member of the seven transmembrane receptor family consist of 10 receptors that are activated by Wnt family of lipo-glycoproteins. The Wnt/ FZD signaling is involved in a variety of biological processes and its dysregulation have been implicated in cancer development. FZD4 protein contains the N-terminal signal peptide (aa 1-36) that assurances proper membrane insertion of the protein, an extracellular cysteine rich domain (CRD; aa 40-161), which creates the binding site for WNT ligands, a seven-pass transmembrane domain (aa 161-221) that gives rise to three intracellular loops, three extracellular loops and a C- terminal domain (aa 221-537). The CRD domain is necessary to bind WNT ligands or Norrin ligand leading to initiation of distinct downstream signaling pathways. (Schulte G., 2010).


Expression	In human, FZD4 is a ubiquitous protein. It is expressed in brain, ovary, liver, pancreas, brain, colon, heart, skeletal muscle, endothelial cells, endometrium, bone marrow, prostate, spleen, breast (www.ncbi.nlm.nih.gov).


	Figure 2: Visualization of FZD4/WNT10B interaction in MCF7 adherent (top) and tumorsphere (bottom) by proximity ligation assay (Lazzaroni et al.,2016).

Localisation	FZD4 is localized on the plasma membrane surface. It can be internalized through both constitutive and agonist dependent endocytosis in response to Wnt5a stimulation (Chen W. et al., 2003).


	Figure 3. Schematic illustrating the activation of βcatenin via the FZD4 receptor.

Function	FZD4 is a member of Frizzled gene family involved in neuronal, follicle, cardiomyocyte and retinal vascular development, likewise its dysregulated expression lead to cancer and other diseases. Depending on the cellular contest, FZD4 interacts with different WNT ligands, leading to the activation of Wnt/β catenin signaling and sometimes non canonical Wnt/Ca²⁺ signaling. Wnt/β catenin signaling is activated when WNT ligands bind CDR FZD/Low-density lipoprotein receptor-related protein5/6 ( LRP5/ LRP6) complex, in this case CTNNB1 (β-catenin) degradation complex becomes inactivated, resulting in stabilization of β-catenin that can translocate in the nucleus, where it interacts with LEF1 (TCF/LEF) transcription factor, inducing the transcription of target genes (Clevers H., 2006). Recently, WNT10B/FZD4 interaction in the MCF7 breast cancer cell line suggests an autocrine activation of Wnt signalling in this cell line model (Lazzaroni F. et al, 2016). In melanoma FZD4 binds WNT5A and stimulates tumor invasion through activation of βcatenin signaling (Grossman A. et al., 2013), while in acute myeloid leukemia the interaction between WNT3A and FZD4 induce higher resistance against apoptosis (Tickenbrock L. et al., 2008). WNT2, WNT5A/ WNT5B and WNT11 via FZD4 and FZD6 induced non canonical Wnt signaling activation that regulates cardiomyocite differentiation (Mazzotta S. et al., 2016) FZD4 is also the only FZD family member that binds selectively a growth factor called NDP (Norrin) and regulates endothelial cells growth during retinal vascular development. In retina, the binding of Norrin with FZD4 conjugated with LRP5 co-receptor and protein TSPAN12 (Tetraspanin-12), results in activation of βcatenin signalling (Schulte G., 2010), alteration in one of this gene is associated with Familial Exudative Vitreoretinopathy.
Homology	The FZD4 gene is conserved in chimpanzee, mouse, Rhesus monkey, dog, cow, rat, chicken, zebrafish and frog.

Mutations

Germinal

Several types of mutations (missense, nonsense, small deletions) have been reported for the human FZD4 gene and are related to the familial exudative vitreoretinopathy (FEVR). Among these mutations, different heterozygous substitutions have been reported: M342V, W335C, R417, I256V, P33S, G36N, H69Y, M105T, M105V, C181R, C204R, C204Y, C45Y, Y58C, W226X, and G488D (Zhang K. et al., 2011; Kondo H. et al. 2003; Quin et al., 2005) It has also been described a loss of function mutation of FZD4 with nucleotides 1479-1484 deletion in two cases of FEVR, resulting in the lacking of met493 and trp494 that leads to a frameshift and creates a stop codon at residue 533 (Robitaille J. et al.,2002).

Implicated in


Entity	Familial Exudative Vitreoretinopathy (FEVR)
Note	Familial Exudative Vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by incomplete development of the retinal vasculature. It is possible to distinguish two forms of FEVR: one with dominant autosomal inheritance and one with X-linked recessive inheritance (Gilmour DF., 2015). Autosomal inheritance has been associated with mutation of FZD4, LRP5 or Tetraspanin 12 (TSPAN12) genes, while X-linked recessive inheritance is due to mutation of Norrin gene (NPD) that it is also involved in other ocular disease. Several FZD4 mutations were connected with FEVR, many of which were found in the extracellular portion of the protein. Kaykas et al., have shown how some FZD4 mutations in FEVR lead to the retention of mutated protein within the endoplasmic reticulum (ER), where it is recognized by endoplasmic-reticulum-associated protein degradation (ERAD) and degraded, not allowing its exposure on the plasma membrane. They also demonstrated that oligomerization of mutants and wild-type FZD4 in the ER reduces the FZD4 function by preventing a sufficient amount of FZD4 from reaching the cell membrane and inhibits its signaling. This dominant-negative effect can partly explain the pathological mechanism that causes the disease phenotype, in patients with heterozygous FZD4 mutations. Mutations that do not cause retention in ER of mutated protein, induce a conformational modification of the CRD FZD4 that doesn't permit the biding to its ligands or downstream targets.


Entity	Acute myeloid leukemia (AML)
Note	It was demonstrated that FZD4 represents one of the mechanism of canonical or non canonical Wnt signaling activation in the pathogenesis of AML. Recently microarray analysis confirmed a higher expression of FZD4 in primary AML blast cells. (Beghini A. et al., 2012). Tickenbrock, A. et al, also showed FZD4 overexpression in primary AML blasts, both in the presence or absence of FLT3 mutations. They also showed a canonical Wnt pathway activation due at specific WNT3A/FZD4 interaction, that leads to the stabilization of β-catenin and induces higher resistance against apoptosis. It was observed an involvement of FZD4 in differentiation of AML cell line mediated by 6-benzylthioinosine (6-BT) treatment. 6-BT treatment results in downregulation of canonical Wnt molecules and up-regulation of transcriptional level of the non canonical Wnt ligand Wnt5a and receptors FZD2, FZD4, FZD5, resulting in activation of Wnt/Ca²⁺ pathway ( Zang S. et al., 2014).


Entity	Non small cell lung cancer (NSCLC)
Note	Recently several studies have reported that single nucleotide polymorphisms (SNPs) of FZD4 gene can influence recurrence and survival of early stage NSCLC patients treated with only surgery or in combination with chemotherapy. miR-related SNP (rs713065) in the 3?UTR region of FZD4 gene is associated with decreased risk of death in early stage NSCLC patients treated with only surgery, while it is related to increased risk of death in patients treated with surgery plus chemotherapy (Pu X. et al., 2013). This FZD4-miR-SNP specifically interacts with MIR204 which acts as a tumor suppressor and inhibits the expression of FZD4 and transduction of Wnt/βcatenin signalling (Lin J. et al, 2017).) This FZD4-miR-SNP specifically interacts with miR-204 which acts as a tumor suppressor and inhibits the expression of FZD4 and transduction of Wnt/βcatenin signalling (Lin J. et al, 2017). Coscio A. et al, demonstrated that miR-SNP (rs10898564) of FZD4 is most significantly associated with increased recurrence and death risk in NSCLC patients treated with only surgery but not in patients treated with surgery and chemotherapy. These reports suggest a potential role of FZD4-SNPs as predictive biomarkers for both recurrence and survival in early stage NSCLC patients.


Entity	Prostate cancer
Note	In prostate cancer cells have been shown activation of Wnt signalling through FZD4 leading to epithelial-to-mesenchymal transition (EMT) and loss of cell adhesion (Gupta S. et al., 2010; Acevedo VD et al., 2007).


Entity	Breast cancer
Note	Recently Lazzaroni F. et al. evidenced an autocrine activation of Wnt signalling in breast cancer cell line model. In MCF7 cell line model they identified the WNT10B/FZD4 interacting complex using the in situ proximity ligation assay and a dose dependent reduction of WNT10B/FZD4 complex after the treatment with pharmacological inhibitor of porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins.


Entity	Liver cancer
Note	It was revealed that Let7b microRNA inhibit Wnt/β-catenin signaling pathway via downregulation of FZD4 in liver cancer cell, resulting in a reduction of proliferation, invasion, migration of liver cancer cells and reduction in the amount of cancer stem cells in liver (Cai H.et al 2017).


Entity	Glioblastoma
Note	Microarray analysis in U87R4 invasive glioblastoma cell line reported an overexpression of FZD4, which actives Wnt/β catenin signalling pathway and promotes stemness and invasiveness of glioblastoma cells. (Jin X. et al. 2011).


Entity	Medulloblastoma
Note	Recently evidences showed an involvement of Norrin/FZD4 signaling pathway in the cerebellar tumor medulloblastoma (MB) initiation. In this tumor, Norrin/FZD4 pathway acts as anti-tumor signal in the preneoplastic niche, in fact loss of function of Norrin/FZD4 signaling in the endothelian cells promotes the formation of preneoplastic lesion of MB and their progression to malignancies (Bassett E. et al., 2016).


Entity	Bladder cancer
Note	FZD4 is a target of miR-493 in the bladder cancer. It was observed a down-regulated expression of miR-493 in the bladder cancer tissue in comparison with normal bladder tissue. MIR493 transfection in the T24 or J82 bladder cancer cell line inhibits FZD4 and Rho4 expression, resulting in the inhibition of cell motility and migration These results, suggested that miR-493 represent a new tumor suppressor in the bladder cancer (Ueno K. et al., 2012).


Entity	Melanoma
Note	It was reported that in melanoma cells Wnt signalling activation through FZD4 promotes tumor cell invasion and metastasis. WNT5a binds FZD4/LRP6 receptor complex and actives the guanosine triphosphatase adenosine diphosphate ribosylation factor 6 ( ARF6), leading to the disruption of N-cadherin-βcatenin complex and accumulation of nuclear βcatenin, which increases the transcription of its target genes and stimulates melanoma invasion (Grossman A. et al., 2013)


Entity	Chronic Myeloid Leukemia
Note	Agarwal P. et al., revealed a role of FZD4 in Wnt-mediated regulation of CML progenitor growth and their resistance to tyrosine kinase inhibitor (TKI) treatment. Silencing of FZD4 expression in combination with Nilotinib (NIL) treatment reduces Wnt signalling activation and the colony forming capacity of CML cells.


Entity	Colorectal cancer
Note	Expression of FZD4 in colorectal cancer and its binding with the Norrin ligand, produced by the same cells and endothelial tumor cells, activates β-catenin signalling and regulates angiogenesis in the colorectal cancer microenvironment (K. Platinus et al. 2014).

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Citation

This paper should be referenced as such :

Beghini A, Cassaro A

FZD4 (frizzled class receptor 4);

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Genes/FZD4ID40655ch11q14.html

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]

t(11;11)(q13;q14) FZD4/LAMTOR1

External links

	Nomenclature
HGNC (Hugo)	FZD4 4042
	Cards
Atlas	FZD4ID40655ch11q14
Entrez_Gene (NCBI)	FZD4 8322 frizzled class receptor 4
Aliases	CD344; EVR1; FEVR; FZD4S;
	Fz-4; Fz4; FzE4; GPCR; hFz4
GeneCards (Weizmann)	FZD4
Ensembl hg19 (Hinxton)	ENSG00000174804 [Gene_View]
Ensembl hg38 (Hinxton)	ENSG00000174804 [Gene_View] ENSG00000174804 [Sequence] chr11:86945675-86955398 [Contig_View] FZD4 [Vega]
ICGC DataPortal	ENSG00000174804
TCGA cBioPortal	FZD4
AceView (NCBI)	FZD4
Genatlas (Paris)	FZD4
WikiGenes	8322
SOURCE (Princeton)	FZD4
Genetics Home Reference (NIH)	FZD4
	Genomic and cartography
GoldenPath hg38 (UCSC)	FZD4 - chr11:86945675-86955398 - 11q14.2 [Description] (hg38-Dec_2013)
GoldenPath hg19 (UCSC)	FZD4 - 11q14.2 [Description] (hg19-Feb_2009)
Ensembl	FZD4 - 11q14.2 [CytoView hg19] FZD4 - 11q14.2 [CytoView hg38]
Mapping of homologs : NCBI	FZD4 [Mapview hg19] FZD4 [Mapview hg38]
OMIM	133780 604579
	Gene and transcription
Genbank (Entrez)	AB032417 AB054881 AK025516 AK025791 AK292768
RefSeq transcript (Entrez)	NM_012193
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)	FZD4
Cluster EST : Unigene	Hs.591968 [ NCBI ]
CGAP (NCI)	Hs.591968
Alternative Splicing Gallery	ENSG00000174804
Gene Expression	FZD4 [ NCBI-GEO ] FZD4 [ EBI - ARRAY_EXPRESS ] FZD4 [ SEEK ] FZD4 [ MEM ]
Gene Expression Viewer (FireBrowse)	FZD4 [ Firebrowse - Broad ]
SOURCE (Princeton)	Expression in : [Datasets] [Normal Tissue Atlas] [carcinoma Classsification] [NCI60]
Genevestigator	Expression in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	8322
GTEX Portal (Tissue expression)	FZD4
Human Protein Atlas	ENSG00000174804-FZD4 [pathology] [cell] [tissue]
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	Q9ULV1 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction]
NextProt	Q9ULV1 [Sequence] [Exons] [Medical] [Publications]
With graphics : InterPro	Q9ULV1
Splice isoforms : SwissVar	Q9ULV1
PhosPhoSitePlus	Q9ULV1
Domaine pattern : Prosite (Expaxy)	FZ (PS50038) G_PROTEIN_RECEP_F2_4 (PS50261)
Domains : Interpro (EBI)	Frizzled/SFRP Frizzled/Smoothened_TM Frizzled_dom Frizzled_dom_sf FZD4 GPCR_2-like
Domain families : Pfam (Sanger)	Frizzled (PF01534) Fz (PF01392)
Domain families : Pfam (NCBI)	pfam01534 pfam01392
Domain families : Smart (EMBL)	FRI (SM00063) Frizzled (SM01330)
Conserved Domain (NCBI)	FZD4
DMDM Disease mutations	8322
Blocks (Seattle)	FZD4
PDB (SRS)	5BPB 5BPQ 5BQC 5BQE 5CL1 5CM4 5UWG
PDB (PDBSum)	5BPB 5BPQ 5BQC 5BQE 5CL1 5CM4 5UWG
PDB (IMB)	5BPB 5BPQ 5BQC 5BQE 5CL1 5CM4 5UWG
PDB (RSDB)	5BPB 5BPQ 5BQC 5BQE 5CL1 5CM4 5UWG
Structural Biology KnowledgeBase	5BPB 5BPQ 5BQC 5BQE 5CL1 5CM4 5UWG
SCOP (Structural Classification of Proteins)	5BPB 5BPQ 5BQC 5BQE 5CL1 5CM4 5UWG
CATH (Classification of proteins structures)	5BPB 5BPQ 5BQC 5BQE 5CL1 5CM4 5UWG
Superfamily	Q9ULV1
Human Protein Atlas [tissue]	ENSG00000174804-FZD4 [tissue]
Peptide Atlas	Q9ULV1
HPRD	05203
IPI	IPI00387029 IPI00977659
	Protein Interaction databases
DIP (DOE-UCLA)	Q9ULV1
IntAct (EBI)	Q9ULV1
FunCoup	ENSG00000174804
BioGRID	FZD4
STRING (EMBL)	FZD4
ZODIAC	FZD4
	Ontologies - Pathways
QuickGO	Q9ULV1
Ontology : AmiGO	amyloid-beta binding vasculogenesis protein binding plasma membrane plasma membrane plasma membrane integral component of plasma membrane cell-cell junction G-protein coupled receptor signaling pathway Wnt signaling pathway, calcium modulating pathway Wnt signaling pathway, calcium modulating pathway sensory perception of sound cell surface negative regulation of cell-substrate adhesion integral component of membrane Wnt signaling pathway Wnt signaling pathway Wnt-protein binding Wnt-protein binding cytokine binding PDZ domain binding PDZ domain binding neuron differentiation dendrite clathrin-coated vesicle membrane clathrin-coated endocytic vesicle membrane regulation of vascular endothelial growth factor receptor signaling pathway ubiquitin protein ligase binding locomotion involved in locomotory behavior substrate adhesion-dependent cell spreading extracellular matrix-cell signaling non-canonical Wnt signaling pathway non-canonical Wnt signaling pathway signaling receptor activity progesterone secretion protein homodimerization activity Wnt-activated receptor activity Wnt-activated receptor activity positive regulation of JUN kinase activity protein-containing complex binding positive regulation of transcription, DNA-templated protein heterodimerization activity positive regulation of DNA-binding transcription factor activity canonical Wnt signaling pathway canonical Wnt signaling pathway canonical Wnt signaling pathway Wnt signaling pathway, planar cell polarity pathway membrane organization retina vasculature morphogenesis in camera-type eye retina vasculature morphogenesis in camera-type eye cerebellum vasculature morphogenesis retinal blood vessel morphogenesis cellular response to retinoic acid positive regulation of neuron projection arborization cellular response to leukemia inhibitory factor
Ontology : EGO-EBI	amyloid-beta binding vasculogenesis protein binding plasma membrane plasma membrane plasma membrane integral component of plasma membrane cell-cell junction G-protein coupled receptor signaling pathway Wnt signaling pathway, calcium modulating pathway Wnt signaling pathway, calcium modulating pathway sensory perception of sound cell surface negative regulation of cell-substrate adhesion integral component of membrane Wnt signaling pathway Wnt signaling pathway Wnt-protein binding Wnt-protein binding cytokine binding PDZ domain binding PDZ domain binding neuron differentiation dendrite clathrin-coated vesicle membrane clathrin-coated endocytic vesicle membrane regulation of vascular endothelial growth factor receptor signaling pathway ubiquitin protein ligase binding locomotion involved in locomotory behavior substrate adhesion-dependent cell spreading extracellular matrix-cell signaling non-canonical Wnt signaling pathway non-canonical Wnt signaling pathway signaling receptor activity progesterone secretion protein homodimerization activity Wnt-activated receptor activity Wnt-activated receptor activity positive regulation of JUN kinase activity protein-containing complex binding positive regulation of transcription, DNA-templated protein heterodimerization activity positive regulation of DNA-binding transcription factor activity canonical Wnt signaling pathway canonical Wnt signaling pathway canonical Wnt signaling pathway Wnt signaling pathway, planar cell polarity pathway membrane organization retina vasculature morphogenesis in camera-type eye retina vasculature morphogenesis in camera-type eye cerebellum vasculature morphogenesis retinal blood vessel morphogenesis cellular response to retinoic acid positive regulation of neuron projection arborization cellular response to leukemia inhibitory factor
Pathways : KEGG	Wnt signaling pathway Hippo signaling pathway Melanogenesis HTLV-I infection Pathways in cancer Proteoglycans in cancer Basal cell carcinoma
REACTOME	Q9ULV1 [protein]
REACTOME Pathways	R-HSA-8856828 [pathway]
NDEx Network	FZD4
Atlas of Cancer Signalling Network	FZD4
Wikipedia pathways	FZD4
	Orthology - Evolution
OrthoDB	8322
GeneTree (enSembl)	ENSG00000174804
Phylogenetic Trees/Animal Genes : TreeFam	FZD4
HOVERGEN	Q9ULV1
HOGENOM	Q9ULV1
Homologs : HomoloGene	FZD4
Homology/Alignments : Family Browser (UCSC)	FZD4
	Gene fusions - Rearrangements
Fusion : Mitelman	FZD4/LAMTOR1 [11q14.2/11q13.4]
Fusion Portal	FZD4 11q14.2 LAMTOR1 11q13.4 BRCA
Fusion Portal	FZD4 11q14.2 RP11-115C10.1 PRAD
Fusion : Quiver	FZD4
	Polymorphisms : SNP and Copy number variants
NCBI Variation Viewer	FZD4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)	FZD4
dbVar	FZD4
ClinVar	FZD4
1000_Genomes	FZD4
Exome Variant Server	FZD4
ExAC (Exome Aggregation Consortium)	ENSG00000174804
GNOMAD Browser	ENSG00000174804
Varsome Browser	FZD4
Genetic variants : HAPMAP	8322
Genomic Variants (DGV)	FZD4 [DGVbeta]
DECIPHER	FZD4 [patients] [syndromes] [variants] [genes]
CONAN: Copy Number Analysis	FZD4
	Mutations
ICGC Data Portal	FZD4
TCGA Data Portal	FZD4
Broad Tumor Portal	FZD4
OASIS Portal	FZD4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMIC	FZD4 [overview] [genome browser] [tissue] [distribution]
Mutations and Diseases : HGMD	FZD4
LOVD (Leiden Open Variation Database)	Whole genome datasets
LOVD (Leiden Open Variation Database)	LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)	Mendelian genes
LOVD (Leiden Open Variation Database)	Eye diseases - LOVD
BioMuta	search FZD4
DgiDB (Drug Gene Interaction Database)	FZD4
DoCM (Curated mutations)	FZD4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)	FZD4 (select a term)
intoGen	FZD4
NCG5 (London)	FZD4
Cancer3D	FZD4(select the gene name)
Impact of mutations	[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
	Diseases
OMIM	133780 604579
Orphanet	7036 11941 12154
DisGeNET	FZD4
Medgen	FZD4
Genetic Testing Registry	FZD4
NextProt	Q9ULV1 [Medical]
TSGene	8322
GENETests	FZD4
Target Validation	FZD4
Huge Navigator	FZD4 [HugePedia]
snp3D : Map Gene to Disease	8322
BioCentury BCIQ	FZD4
ClinGen	FZD4 (curated)
	Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD	8322
Chemical/Pharm GKB Gene	PA28459
Clinical trial	FZD4
	Miscellaneous
canSAR (ICR)	FZD4 (select the gene name)
	Probes
	Litterature
PubMed	80 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
CoreMine	FZD4
EVEX	FZD4
GoPubMed	FZD4
iHOP	FZD4

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Search in all EBI NCBI

indexed on : Thu Aug 16 11:53:38 CEST 2018

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