FZD4
protein-codingfrizzled class receptor 4, the group of CD molecules|G protein-coupled receptors, Class F frizzled
Gene summary
This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the Wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. This protein may play a role as a positive regulator of the Wingless type MMTV integration site signaling pathway. A transcript variant retaining intronic sequence and encoding a shorter isoform has been described, however, its expression is not supported by other experimental evidence. [provided by RefSeq, Jul 2008]
- EVR1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007589
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019516
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0007589
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007589
Submitter: PanelApp Australia
Inheritance Pattern: SD
Disease ID:MONDO:0007589
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007589
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019631
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:1040041
Submitter: ClinGen
*FZD4* was first reported in relation to autosomal dominant familial exudative vitreoretinopathy (FEVR) in 2002 (Robitaille et al., PMID: 12172548). FEVR is characterized by abnormal development of the retinal blood vessels, leading to incomplete vascularization of the peripheral retina. Features can include retinal detachment, vascular leakage, vitreoretinal traction, macular folds, peripheral avascular zones, retinal exudates, and vision loss/blindness. FEVR is known to have a high degree of inter- and intra-familial clinical variability as well as reduced penetrance. *FZD4* is one of multiple FEVR genes, and *FZD4* is associated with the disease entity exudative vitreoretinopathy 1 (MIM# 133780). *FZD4* has also been associated with retinopathy of prematurity (ROP) (MIM# 133780, described in MacDonald et al., 2005. PMID:15733276), however FEVR and ROP have great deal of clinical overlap, and these conditions can co-occur. Studies suggest that a portion of severe ROP cases harbor disease-causing *FZD4* variants and represent cases of FEVR in the setting of prematurity (PMID: 26731204). Therefore, this curation has been performed under the disease entity FZD4-related exudative vitreoretinopathy. Twelve heterozygous variants (missense, in-frame indel, nonsense, frameshift, deletion) that have been reported in fifteen probands in seven publications (PMIDs: 12172548, 14507768, 15035989, 15223780, 15488808, 21177847, 23077402) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. Given the reported variable expressivity and reduced penetrance of FEVR, probands were not excluded from the curation if they had family members who were mutation positive but asymptomatic. Three studies showing linkage of the clinical phenotypes to the *FZD4* locus in large pedigrees were available in these publications (PMID:12172548, 15035989, 21177847), and contributed to the scoring of the gene-disease relationship. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, there are limited reports of individuals with biallelic *FZD4* variants with severe FEVR (PMIDs: 18161623, 38361102) or syndromic FEVR with hearing loss and developmental delay (PMID: 35951321). In some cases, the parents are reported to have mild ocular features of FEVR (PMID: 18161623), suggesting that semidominant inheritance can occur. These biallelic cases were not included in the present curation. There is not sufficient evidence in the literature at this time to determine if autosomal recessive syndromic FEVR is a separate disease entity related to *FZD4*. This gene-disease relationship is also supported by experimental evidence, including animal models, protein interactions, expression studies, and *in vitro* functional assays (PMIDs: 15035989, 19837032, 21177847, 27489958). *FZD4* encodes Frizzled-4 (Fz4), a receptor that plays a crucial role in the Norrin/Fz4/Lrp signaling pathway that is essential for normal vascular development. The biochemical function of Fz4 matches that of the LRP5 co-receptor, which is encoded by a gene in which biallelic and monoallelic variants have been reported to cause FEVR (PMID: 15035989). In the mouse retina, Fz4 (Frizzled4) is expressed in vascular cells (endothelial cells & mural cells), photoreceptors, and some inner retinal neurons (PMID:19837032). Mice with biallelic loss of function mutations in *Fzd4* recapitulate human patient phenotypes including abnormal retinal vasculature, impaired vision, and abnormal electroretinogram (PMIDs:15035989, 19837032). In addition, studies with *Fzd4* heterozygous mice indicate that haploinsufficiency results in abnormal retinal vasculature development (PMID: 27489958). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between *FZD4* and autosomal dominant FZD4-related exudative vitreoretinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on April 4th, 2024 (SOP Version 10).
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Digenic inheritance (with LRP5 has been reported)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FZD4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012193.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 95 | 96 | |||
| missense | 5 | 19 | 258 | 22 | 1 | 305 |
| nonsense | 15 | 7 | 22 | |||
| start loss | 0 | |||||
| frameshift | 34 | 8 | 3 | 45 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 55 | 34 | 263 | 117 | 1 | 470 |
Highest pathogenic variant AF is 0.000021685415
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036325.2 | 2 | MANE Select | |
| Ensembl | ENSP00000434034.1 | 2 | MANE Select | |
| Ensembl | ENSP00000787985.1 | 2 | Standard | |
| Ensembl | ENSP00000787986.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gastric cancer - Homo sapiens (human)
- mTOR signaling pathway - Homo sapiens (human)
- Cushing,s syndrome - Homo sapiens (human)
- Breast cancer - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
Biological Process
- vasculogenesis
- G protein-coupled receptor signaling pathway
- Wnt signaling pathway, calcium modulating pathway
- sensory perception of sound
- negative regulation of cell-substrate adhesion
Molecular Function
- amyloid-beta binding
- G protein-coupled receptor activity
- protein binding
- Wnt-protein binding
- cytokine binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- cell-cell junction
- cell surface
- dendrite
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000531380
- Coding exons
- 2
- Length
- 9713
- Individuals with no LoFs
- 125735
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 13
- Defined
- 125748
- p
- 0.0000517
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.733 | 255 | 290 | 0.879 | 0.0000149 | 3512 |
| Missense (PolyPhen) | 62 | 101.43 | 0.61127 | 1320 | ||
| Synonymous | -0.567 | 121 | 113 | 1.07 | 0.00000610 | 1081 |
| Loss of Function | 3.38 | 1 | 15.2 | 0.0657 | 6.63e-7 | 207 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.;
- Disease
- DISEASE: Vitreoretinopathy, exudative 1 (EVR1) [MIM:133780]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. In many ways the disease resembles retinopathy of prematurity but there is no evidence of prematurity or small birth weight in the patient history. {ECO:0000269|PubMed:12172548, ECO:0000269|PubMed:14507768, ECO:0000269|PubMed:15035989, ECO:0000269|PubMed:15223780, ECO:0000269|PubMed:15370539, ECO:0000269|PubMed:15488808, ECO:0000269|PubMed:15733276, ECO:0000269|PubMed:15981244, ECO:0000269|PubMed:17093393, ECO:0000269|PubMed:17955262, ECO:0000269|PubMed:19172507, ECO:0000269|PubMed:19324841, ECO:0000269|PubMed:20340138}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.210
Intolerance Scores
- LoFtool
- 0.0584
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.7
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.961
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |