• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
FZD4 (HGNC:4042) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
frizzled class receptor 4
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
EVR1
Alias symbols
CD344
%HI
22.13(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.97(Read more about gnomAD pLI score)
LOEUF
0.31(Read more about gnomAD LOEUF score)
Cytoband
11q14.2
Genomic Coordinates
GRCh37/hg19: chr11:86656721-86666437 NCBI Ensembl UCSC
GRCh38/hg38: chr11:86945679-86955395 NCBI Ensembl UCSC
MANE Select Transcript
NM_012193.4 ENST00000531380.2 (Read more about MANE Select)
Function
Receptor for Wnt proteins (PubMed:30135577). Most 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 (PubMed:30135577). Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP) (By similarity). In retina, it can be activated by Wnt protein-binding a... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-1107
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
01/25/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • familial exudative vitreoretinopathy (FEVR) Monarch
HI Evidence:
  • PUBMED: 12172548
    Robitaille et al. (2002) describe a large Canadian family of British descent with autosomal dominant familial exudative vitreoretinopathy (FEVR). A six nucleotide deletion (reported as nt 1479-1484) was detected in two family members, resulting in loss of two conserved amino acids, p.Met493_Trp494del. The variant haplotype segregated with disease in 25 family members, although some individuals were clinically unaffected, and only exhibited retinal abnormalities by intravenous fluorescein angiography. An additional FZD4 variant (c.1501-1502del, p.Leu501TyrfsTer533) was found to segregate with disease in another unrelated family with FEVR (no pedigree or further detail provided). The authors tested the function of these sequence alterations in transfection experiments and functional assay with X. laevis embryo lysates, demonstrating that Leu501TyrfsTer533 fails to localize to the plasma membrane, and both variants result in impaired signaling through CAMKII and PKC. Thus, the authors conclude that mutations leading to loss of function of FZD4 cause FEVR.
  • PUBMED: 14507768
    Kondo et al. (2003) sequenced the FZD4 gene in 24 Japanese patients diagnosed with FEVR. The p.W319* variant was identified de novo in one proband with sporadic FEVR, and was absent in the parents, although parental relationships were not confirmed. While the W319* variant is not predicted to undergo nonsense-mediated decay (NMD), subsequent functional studies (Qin et al., 2008, PMID: 17955262) have demonstrated that this variant results in a near complete loss of Norrin signaling. The R417Q variant was identified in 2 unrelated probands, and was shown to segregate in 5 affected individuals across the 2 families. Additionally, the M105V variant and the G488D variant were each detected in one FEVR family, and demonstrated segregation with the phenotype. Additional studies have characterized the function of these variants and demonstrated reduced signaling capacity and/or impaired localization to the plasma membrane (Xu et al., 2004, PMID: 15035989; Qin et al., 2008, PMID: 17955262; Milhelm et al., 2014, PMID: 24744206).
  • PUBMED: 25711638
    Salvo et al. (2015) perform next-generation sequencing (NGS) targeting five FEVR-associated genes (FZD4, LRP5, NDP, TSPAN12, and ZNF408). A cohort of 92 probands with FEVR was included in the study. They identify several FZD4 mutations, including p.E40* and p.E42*, both of which are predicted to undergo NMD. Both were familial cases with additional affected family members, but segregation studies were not performed for these families.
  • PUBMED: 26244290
    Seo et al. (2015) describe genetic testing to identify the molecular cause of FEVR in 51 unrelated individuals diagnosed at the Seoul National University Children’s Hospital over a 5 year period. All patients were negative for mutations in the NDP gene (causative for X-linked FEVR), and the FZD4, LRP5 and TSPAN12 genes were analyzed sequentially. FZD4 mutations were identified in 13 unrelated probands, including c.160C>T p.Gln54* nonsense variant, which is predicted to undergo NMD. One patient had a deletion of the entire FZD4 gene, detected by MLPA; the extent of the deletion and potential involvement of other genes was not interrogated. Additional variants included missense, and other frameshift and nonsense variants not predicted to trigger NMD. Inheritance information was not provided for the majority of cases.
  • PUBMED: 34860240
    Tao et al. (2021) performed NGS sequencing of 6 genes (FZD4, LRP5, NDP, TSPAN12, KIF11, ZNF408) in 120 Chinese probands with FEVR. They identify FZD4 variants in 25 probands, including frameshift mutation p.P14Sfs*44 in one patient (predicted to undergo NMD), as well as p.M105V in two patients. Inheritance information is not specified.
  • PUBMED: 35394490
    Lu et al. (2022) describe genetic testing in 651 probands with a clinical diagnosis of FEVR. They detect the p.Glu40* nonsense variant (predicted to undergo NMD) in 2 unrelated patients. Additionally, they report deletion of FZD4 exons 1-2 (i.e. entire gene deletion, since there are 2 exons total in the gene) found in 4 unrelated patients. Specific inheritance information was not provided, and no further details regarding the boundaries of the CNVs and involvement of additional genes were available. Trp319* was also identified in two individuals with FEVR. This variant has been characterized in an additional study (Qin et al., 2008, PMID: 17955262) as resulting in loss of function, with nearly complete abrogation of Norrin signaling by reporter assay.
HI Evidence Comments:
FZD4 is one of several genes involved in Norrin signaling in the retina and associated with familial exudative vitreoretinopathy (FEVR). FEVR is characterized by incomplete or absent vascularization of the peripheral retina, which can lead to impaired vision. Penetrance of this disorder is reportedly high, but highly variable phenotypic expression is observed, including among members of the same family (Lu et al., 2022). Some individuals may be clinically asymptomatic but show features of the disorder, such as avascular regions of the retina, by intravenous fluorescein angiography. Variants in FZD4 are identified in 15-20% of FEVR families (PMID: 34199009 Huang 2021). The FZD4 gene contains only two exons, with the first exon encoding amino acids 1-95, and the second exon encoding amino acids 96-537 and the termination codon. Given this gene structure, the majority of reported nonsense and frameshift variants are not predicted to undergo nonsense-mediated decay (NMD). This haploinsufficiency curation considered variants predicted to result in a premature termination codon located more than 50 bp away from the end of exon 1 (up to and including amino acid residue 78), and therefore predicted to be subject to NMD. Additional variants considered for haploinsufficiency scoring had functional evidence from one or more studies supportive of a loss of function mechanism. There are numerous additional variants reported that are not documented here, some of which may also be resulting in loss of function. Additional information includes: Huang et al. (2021) report deletions of the entire FZD4 gene in four patients diagnosed with FEVR. Deletions ranged in size from 150 kb to 4.5 Mb, and each involved at least one other gene in addition to FZD4. The deletions were all inherited from affected fathers. The authors note that the phenotypes of the probands carrying deletions were not more severe than those seen in patients with other variant types. Of note, based on the names and institutional affiliations of the authors, these four deletions may be the same as those reported in Lu et al., 2022, although this is not explicitly indicated in either publication. Functional studies: Xu et al. (2004, PMID: 15035989) report that fz4-/- mice show numerous retinal vascular abnormalities, similar to some human features of FEVR. Of note, heterozygous fz4+/- mice showed no phenotypic differences from wild type mice. The authors also identify M105V and M157V missense variants in two FEVR probands; the M105V variant was in a simplex case, with no further inheritance information provided, while the M157V variant segregated in three other affected relatives, with one deceased individual who was affected demonstrated to be an obligate carrier, although genetic testing could not be performed. They further characterize these variants, along with the M493_W494del variant (reported in Robitaille et al. and referred to here as delMW) and show that the missense variant proteins are produced at levels similar to wild type, while the delMW variant protein is observed at levels several fold lower than wild type. All three variant proteins show severely impaired Norrin signaling by reporter assay. The delMW variant has nearly undetectable reporter activity, while the two missense variants have <10% activity of wild type. Qin et al. (2008 PMID: 17955262) assess Norrin signaling of FZD4 variants (M105V, W319*, R417Q) via a stable reporter assay. All variants showed impaired Norrin signaling, with the nonsense exerting a stronger effect than the missense variants, abrogating nearly all reporter activity. The M105V variant showed approximately 70% activity compared to wildtype, and the R417Q variant showed approximately 50% activity compared to wildtype. Milhelm et al. (2014 PMID: 24744206) examine protein localization and stability of FZD4 variants through transfection experiments with confocal microscopy and western blotting. They show that several FZD4 variants, including the G488D variant fail to localize to the plasma membrane, and are retained in the ER. The M105V variant showed partial mislocalization, with some protein present at the plasma membrane and some retained in the ER. Furthermore, they showed evidence of protein folding defects resulting from these mutations, with polyubiquitination suggesting that the mutant proteins are targeted for degradation. Further studies of some mutant proteins co-expressed with wildtype FZD4 support a haploinsufficiency model, as they show that the mutant proteins do not dimerize with wildtype FZD4 and do not cause wildtype FZD4 to be retained in the ER, thus ruling out a dominant negative function. Several studied variants showed normal protein localization to the plasma membrane, including the R417Q variant.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
A triplosensitive phenotype has yet to be reported for this gene.

Genomic View

Select assembly: (NC_000011.9) (NC_000011.10)