FZD<sub>4</sub> | Class Frizzled GPCRs | IUPHAR/BPS Guide to PHARMACOLOGY

FZD4

Target id: 232

Nomenclature: FZD4

Family: Class Frizzled GPCRs

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for FZD4 in GtoImmuPdb

Gene and Protein Information
Frizzled family G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 537 11q14.2 FZD4 frizzled class receptor 4 14
Mouse 7 537 7 E1 Fzd4 frizzled class receptor 4 37
Rat 7 538 1q32 Fzd4 frizzled class receptor 4
Previous and Unofficial Names
Fz4 | CD344 | EVR1 | exudative vitreoretinopathy 1 | frizzled family receptor 4 | frizzled receptor 4
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Complex structure of Norrin with human Frizzled 4
PDB Id:  5CL1
Resolution:  3.8Å
Species:  Human
References:  31
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human Frizzled 4 Cysteine-Rich Domain (CRD)
PDB Id:  5CM4
Resolution:  2.4Å
Species:  Human
References:  31
Natural/Endogenous Ligands
Wnt

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Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
norrin {Sp: Mouse} Mm Full agonist 8.4 pKd 39
pKd 8.4 [39]
Agonist Comments
Due to the lack of purified and biologically active WNTs little information on the specificity and pharmacology of FZD-WNT interaction is available. Extensive and quantitative binding assays have not been performed with mammalian FZDs. Evidence for the direct activation/interaction of FZD4 with WNT-5A [4,22], WNT-3A [23], WNT-2 [15], WNT-7B [38] and the FZD4 specific ligand Norrin [39] exist.
Antagonist Comments
Amyloid-β peptide binds with high affinity to FZD4-CRD and FZD5-Crd and inhibits β-catenin dependent signalling [20]. sFRP1 interacts with WNTs and FZD4-CRD [6].
Primary Transduction Mechanisms
Transducer Effector/Response
G12/G13 family
Comments:  The involvement of heterotrimeric G proteins is likely but has not yet been addressed for FZD4 in detail.

The following papers contain some information on the FZD4 signalling pathways:
FZD4/non-canonical signalling [22]
FZD4/canonical WNT signalling (β-catenin dependent) [13,22].
References:  13,22
Secondary Transduction Mechanisms
Transducer Effector/Response
G12/G13 family
References:  2
Tissue Distribution
Increased expression in ulcerative colitis.
Species:  Human
Technique:  Microarray analysis
References:  42
Trigeminal ganglion, ciliary ganglion, superior cervical ganglion, adipose tissue, skeletal muscle
Species:  Human
Technique:  Microarray analysis
References:  34
Cervical cancer cell line (HeLa S3).
Species:  Human
Technique:  Northern blot
References:  14
Adult: heart, skeletal muscle, ovary > liver, kidney, spleen, pancreas.
Fetal: kidney > lung
Species:  Human
Technique:  Northern blot
References:  14
Primary endothelial cells, aortic smooth muscle cells.
Species:  Human
Technique:  RT-PCR
References:  21
Colon (colonic mucosa, normal mucose derived colon cells, NCM 460, endothelial cell line (EaHy926), tumorigenic colon cancer cell lines (including RKO and HCT116 but not Colo205)).
Species:  Human
Technique:  RT-PCR
References:  24
Increased expression in prostate cancer.
Species:  Human
Technique:  Immunocytochemistry
References:  1
Brain, oesophagus, auditory system
Species:  Mouse
Technique:  Immunohistochemistry
References:  36
Adult retinal vasculature retina (endothelial cells, mural cells, photoreceptors, and a subset of inner retinal neurons)
Species:  Mouse
Technique:  Immunohistochemistry and AP staining
References:  40
Vena cava, white and brown adipose tissue, adipocytes, skeletal muscle
Species:  Mouse
Technique:  qRT-PCR
References:  28
Hematopoietic progenitor cell line (32/Flt3-ITD).
Species:  Mouse
Technique:  RT-PCR
References:  35
During development: small intestine and colon.
Species:  Mouse
Technique:  in situ hybridisation
References:  10
Cerebellum (Ndph knock-out mice)
Species:  Mouse
Technique:  RT-PCR
References:  18
During development: Midbrain dopaminergic neurons.
Species:  Mouse
Technique:  FACS, quantitative PCR
References:  27
Embryonic lung mesenchyme
Species:  Mouse
Technique:  in situ hybridisation
References:  38
Adult lung epithelial cells
Species:  Mouse
Technique:  Microarray analysis and oligonucleotide microarray
References:  7
Adult: brain, eye, heart, kidney, liver, lung, testis.
Developing brain: choroid plexus.
Species:  Mouse
Technique:  RNAse protection assay, in situ hybridization
References:  37
Ovary cells.
Species:  Rat
Technique:  RT-PCR
References:  24
Tissue Distribution Comments
Pinpointing one of the FZD isoforms in relationship to functional assays is compromised due to the high endogenous expression of various FZD isoforms in many cellular systems.
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of FZD4 receptor internalization in HEK293 cells. This requires Dvl2, β-arrestin 2, PKC and the presence of WNT-5A agonist bound to FZD4.
Species:  Human
Tissue:  HEK293 cells.
Response measured:  FZD4-GFP internalization
References:  4
Measurement of β-catenin stabilization in HEK293 cells. Mouse FZD4 activates the β-catenin signalling (canonical-signalling) pathway after WNT-5A stimulation in the presence of LRP5.
Species:  Human
Tissue:  HEK293 cells.
Response measured:  β-catenin stabilization
References:  22
Measurement of TCF/LEF transcriptional activity, using the TopFlash reporter, in HEK293 cells transfected with mouse FZD4, LRP5 and norrin.
Species:  Human
Tissue:  HEK293 cells.
Response measured:  Activation of TCF/LEF promotor activity.
References:  39
Physiological Functions
The norrin-FZD4 signalling system plays a central role in vascular development in the eye and ear.
Species:  Mouse
Tissue:  Retina, cochlea
References:  39
FZD4 plays a role in intestine development and homeostasis.
Species:  Mouse
Tissue:  Intestine
References:  10
Physiological Consequences of Altering Gene Expression
FZD4 knock-out mice show progressive cerebellar degeneration associated with ataxia, absence of the skeletal muscle sheath around the oesophagus associated with dysfunction, and progressive deafness because of defects in the peripheral auditory system.
Species:  Mouse
Tissue: 
Technique:  Transgenesis
References:  36
FZD4 knock-out mice are infertile and show defective corpora lutea formation and function.
Species:  Mouse
Tissue: 
Technique:  Transgenesis
References:  11
Mice with complete receptor knockout show substantial abnormalities in terms of growth retardation, oesophageal dysfunction and distension, progressive hearing loss and are prone to premature death. Progressive cerebellar degeneration associated with severe ataxia, absence of a skeletal muscle sheath around the lower esophagus associated with progressive esophageal distension and dysfunction, and progressive deafness caused by a defect in the peripheral auditory system unaccompanied by loss of hair cells or other auditory neurons.
Species:  Mouse
Tissue:  Brain, oesophagus
Technique:  Gene knockouts
References:  36
Mice with complete receptor knockout present a defective reproductive phenotype that is characterized by relatively normal ovarian follicular development but exhibits impaired formation and function of corpora lutea. Impaired corpus luteum formation in pregnant mice after day 5.5 p.c.; vascular defects during luteinization; relatively normal ovarian follicular development and responses to eCG/FSH.
Species:  Mouse
Tissue:  Ovaries
Technique:  Gene knockouts
References:  11
Defective intraretinal vasculature with abnormal development of the retinal vasculature as well as vascular defects in the stria vascularis and cerebellum. Mice with complete receptor knockout have retarded endothelial cell migration along the retinal surface and medium to severe impacts on vascularization in the retina, hyaloid artery, stria vascularis and in the cerebellum.
Species:  Mouse
Tissue:  Brain, retina
Technique:  Gene knockouts
References:  39
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Fzd4+|Fzd4tm1Nat|Tg(Sox2-cre)1Amc|Ubbtm2Nat Fzd4tm1Nat/Fzd4+,Ubbtm2Nat/Ubbtm2Nat,Tg(Sox2-cre)1Amc/?
involves: 129 * C57BL/6 * CBA
MGI:108520  MGI:2656537  MGI:98888  MP:0000260 abnormal angiogenesis PMID: 19837032 
Fzd4tm1Nat|Fzd4tm2.1Nat|Tg(Tek-cre)1Ywa Fzd4tm1Nat/Fzd4tm2.1Nat,Tg(Tek-cre)1Ywa/?
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
MGI:108520  MGI:2450309  MP:0004950 abnormal brain vasculature morphology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MP:0004950 abnormal brain vasculature morphology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000886 abnormal cerebellar granule layer PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000849 abnormal cerebellum morphology PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MP:0000849 abnormal cerebellum morphology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0002679 abnormal corpus luteum PMID: 16093361 
Fzd4+|Fzd4tm1Nat|Tg(Sox2-cre)1Amc|Ubbtm2Nat Fzd4tm1Nat/Fzd4+,Ubbtm2Nat/Ubbtm2Nat,Tg(Sox2-cre)1Amc/?
involves: 129 * C57BL/6 * CBA
MGI:108520  MGI:2656537  MGI:98888  MP:0009869 abnormal descending aorta morphology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001664 abnormal digestion PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000469 abnormal esophageal squamous epithelium morphology PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000467 abnormal esophagus morphology PMID: 11425903 
Fzd4tm1Nat|Fzd4tm2.1Nat|Tg(Tek-cre)1Ywa Fzd4tm1Nat/Fzd4tm2.1Nat,Tg(Tek-cre)1Ywa/?
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
MGI:108520  MGI:2450309  MP:0005551 abnormal eye electrophysiology PMID: 19837032 
Fzd4tm1Nat|Fzd4tm2.1Nat|Tg(rx3-cre)1Mjam Fzd4tm1Nat/Fzd4tm2.1Nat,Tg(rx3-cre)1Mjam/?
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MGI:3665327  MP:0005551 abnormal eye electrophysiology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MP:0005551 abnormal eye electrophysiology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001406 abnormal gait PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0003690 abnormal glial cell physiology PMID: 11425903 
Fzd4tm1Nat|Fzd4tm2.1Nat|Tg(Tek-cre)1Ywa Fzd4tm1Nat/Fzd4tm2.1Nat,Tg(Tek-cre)1Ywa/?
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
MGI:108520  MGI:2450309  MP:0009619 abnormal optokinetic reflex PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MP:0009619 abnormal optokinetic reflex PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000042 abnormal organ of Corti PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001504 abnormal posture PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0002792 abnormal retinal vasculature morphology PMID: 15035989 
Fzd4tm1Nat|Fzd4tm2.1Nat|Tg(Tek-cre)1Ywa Fzd4tm1Nat/Fzd4tm2.1Nat,Tg(Tek-cre)1Ywa/?
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
MGI:108520  MGI:2450309  MP:0002792 abnormal retinal vasculature morphology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MP:0002792 abnormal retinal vasculature morphology PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000048 abnormal stria vascularis PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0004368 abnormal stria vascularis vasculature morphology PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000259 abnormal vascular development PMID: 16093361 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001134 absent corpus luteum PMID: 16093361 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0006359 absent startle reflex PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001393 ataxia PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000851 cerebellum hypoplasia PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0004362 cochlear hair cell degeneration PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0004398 cochlear inner hair cell degeneration PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0004404 cochlear outer hair cell degeneration PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0004765 decreased brainstem auditory evoked potential PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0005185 decreased circulating progesterone level PMID: 16093361 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000880 decreased Purkinje cell number PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0009402 decreased skeletal muscle fiber diameter PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001489 decreased startle reflex PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0000371 diluted coat color PMID: 11425903 
Fzd4+|Fzd4tm1Nat|Tg(Sox2-cre)1Amc|Ubbtm2Nat Fzd4tm1Nat/Fzd4+,Ubbtm2Nat/Ubbtm2Nat,Tg(Sox2-cre)1Amc/?
involves: 129 * C57BL/6 * CBA
MGI:108520  MGI:2656537  MGI:98888  MP:0003984 embryonic growth retardation PMID: 19837032 
Fzd4+|Fzd4tm1Nat|Tg(Sox2-cre)1Amc|Ubbtm2Nat Fzd4tm1Nat/Fzd4+,Ubbtm2Nat/Ubbtm2Nat,Tg(Sox2-cre)1Amc/?
involves: 129 * C57BL/6 * CBA
MGI:108520  MGI:2656537  MGI:98888  MP:0008762 embryonic lethality PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0004545 enlarged esophagus PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001728 failure of embryo implantation PMID: 16093361 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001926 female infertility PMID: 16093361 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001914 hemorrhage PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001505 hunched posture PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001133 impaired luteal cell differentiation PMID: 16093361 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0003356 impaired luteinization PMID: 16093361 
Fzd4tm1Nat|Fzd4tm2.1Nat|Tg(Tek-cre)1Ywa Fzd4tm1Nat/Fzd4tm2.1Nat,Tg(Tek-cre)1Ywa/?
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
MGI:108520  MGI:2450309  MP:0006243 impaired pupillary reflex PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MP:0006243 impaired pupillary reflex PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001925 male infertility PMID: 16093361 
Fzd4tm2.1Nat Fzd4tm2.1Nat/Fzd4tm2.1Nat
involves: 129S1/Sv * 129X1/SvJ
MGI:108520  MP:0002169 no abnormal phenotype detected PMID: 19837032 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001289 persistence of hyaloid vascular system PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0002083 premature death PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0006185 retinal hemorrhage PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001407 short stride length PMID: 11425903 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0004363 stria vascularis degeneration PMID: 15035989 
Fzd4tm1Nat Fzd4tm1Nat/Fzd4tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108520  MP:0001263 weight loss PMID: 11425903 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Exudative vitreoretinopathy 1; EVR1
Synonyms: Exudative vitreoretinopathy [Disease Ontology: DOID:0050535]
Familial exudative vitreoretinopathy [Orphanet: ORPHA891]
Disease Ontology: DOID:0050535
OMIM: 133780
Orphanet: ORPHA891
Comments: 
References:  3,5,8-9,16-17,26,29,32-33,41
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift: Deletion Human L501fsX533 A 2-bp deletion in the FZD4 gene results in a frameshift at leu501, creating a stop codon at residue 533 29
In-frame deletion Human M493_W494del 1479-1484del A deletion of the FZD4 gene nucleotides 1479-1484 resulted in deletion of 2 highly conserved amino acids, met493 and trp494. 29
Missense Human I256V 766A>G Heterozygosity for a 766A-G transition in the FZD4 gene, resulting in an ile256-to-val (I256V) substitution 19
Missense Human W335C 1005G>C A heterozygous nucleotide transversion in exon 2 of the FZD4 gene results in a trp335-to-cys (W335C) substitution 25
Missense Human M342V 1026A>G A heterozygous 1026A-G transition in the FZD4 gene results in a met342-to-val (M342V) substitution 41
Missense Human R417Q 1250G>A A heterozygous 1250G-A transition in exon 2 of the FZD4 gene results in an arg417-to-gln (R417Q) substitution. 29
Disease:  Persistent hyperplastic primary vitreous
Orphanet: ORPHA91495
References:  30
Disease:  Retinopathy of prematurity
Synonyms: Exudative vitreoretinopathy 1; EVR1 [OMIM: 133780]
Disease Ontology: DOID:13025
OMIM: 133780
Orphanet: ORPHA90050
Biologically Significant Variants
Type:  Single nucleotide polymorphism
Species:  Human
Description:  In FEVR, wild-type FZD receptors are trapped in the endoplasmic reticulum by oligomerization with mutant FZD4.
References:  12

References

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1. Acevedo VD, Gangula RD, Freeman KW, Li R, Zhang Y, Wang F, Ayala GE, Peterson LE, Ittmann M, Spencer DM. (2007) Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell, 12: 559-571. [PMID:18068632]

2. Arthofer E, Hot B, Petersen J, Strakova K, Jäger S, Grundmann M, Kostenis E, Gutkind JS, Schulte G. (2016) WNT Stimulation Dissociates a Frizzled 4 Inactive-State Complex with Gα12/13. Mol. Pharmacol., 90 (4): 447-59. [PMID:27458145]

3. Canny CL, Oliver GL. (1976) Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch. Ophthalmol., 94 (7): 1114-20. [PMID:947162]

4. Chen W, ten Berge D, Brown J, Ahn S, Hu LA, Miller WE, Caron MG, Barak LS, Nusse R, Lefkowitz RJ. (2003) Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Science, 301: 1391-1394. [PMID:12958364]

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Gunnar Schulte, Jacomijn Dijksterhuis, Julian Petersen, Elisa Arthofer, Belma Hot, Katerina Strakova, Shane Wright, Jana Valnohova, Matthias Lauth.
Class Frizzled GPCRs: FZD4. Last modified on 22/02/2017. Accessed on 17/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=232.