WNT4

Summary

WNT4 (Wnt family member 4, HGNC:12783) is a protein-coding gene on chromosome 1p36.12, encoding Protein Wnt-4 (P56705). Ligand for members of the frizzled family of seven transmembrane receptors.

The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, and is the first signaling molecule shown to influence the sex-determination cascade. It encodes a protein which shows 98% amino acid identity to the Wnt4 protein of mouse and rat. This gene and a nuclear receptor known to antagonize the testis-determining factor play a concerted role in both the control of female development and the prevention of testes formation. This gene and another two family members, WNT2 and WNT7B, may be associated with abnormal proliferation in breast tissue. Mutations in this gene can result in Rokitansky-Kuster-Hauser syndrome and in SERKAL syndrome.

Source: NCBI Gene 54361 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mullerian aplasia and hyperandrogenism (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 78
• Clinical variants (ClinVar): 173 total — 5 pathogenic
• Phenotypes (HPO): 64
• MANE Select transcript: NM_030761

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12783
Approved symbol	WNT4
Name	Wnt family member 4
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	WNT-4
Ensembl gene	ENSG00000162552
Ensembl biotype	protein_coding
OMIM	603490
Entrez	54361

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000290167, ENST00000415567, ENST00000441048, ENST00000901549, ENST00000951124

RefSeq mRNA: 1 — MANE Select: NM_030761 NM_030761

CCDS: CCDS223

Canonical transcript exons

ENST00000290167 — 5 exons

Exon	Start	End
ENSE00000759619	22121445	22121576
ENSE00000759620	22121211	22121353
ENSE00000759621	22117313	22120517
ENSE00001896320	22142846	22143097
ENSE00003517608	22129616	22129851

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 90.71.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3989 / max 181.4463, expressed in 303 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10914	0.7310	205
10915	0.5096	145
10916	0.0660	25
10913	0.0573	25
10912	0.0351	15

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	90.71	gold quality
decidua	UBERON:0002450	89.95	gold quality
type B pancreatic cell	CL:0000169	88.21	silver quality
upper leg skin	UBERON:0004262	86.35	gold quality
lower esophagus mucosa	UBERON:0035834	86.27	gold quality
palpebral conjunctiva	UBERON:0001812	85.32	gold quality
skin of abdomen	UBERON:0001416	84.03	gold quality
skin of leg	UBERON:0001511	81.71	gold quality
zone of skin	UBERON:0000014	81.64	gold quality
right ovary	UBERON:0002118	80.95	gold quality
esophagus mucosa	UBERON:0002469	79.52	gold quality
left ovary	UBERON:0002119	79.01	gold quality
right adrenal gland cortex	UBERON:0035827	78.28	gold quality
cortical plate	UBERON:0005343	78.24	gold quality
skin of hip	UBERON:0001554	77.77	gold quality
gingival epithelium	UBERON:0001949	77.68	gold quality
esophagus squamous epithelium	UBERON:0006920	77.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.40	gold quality
epithelium of esophagus	UBERON:0001976	77.08	gold quality
right adrenal gland	UBERON:0001233	76.98	gold quality
gingiva	UBERON:0001828	76.45	gold quality
ovary	UBERON:0000992	76.13	gold quality
left uterine tube	UBERON:0001303	75.71	gold quality
eye	UBERON:0000970	75.25	gold quality
adrenal cortex	UBERON:0001235	74.60	gold quality
left adrenal gland cortex	UBERON:0035825	74.09	gold quality
left adrenal gland	UBERON:0001234	73.86	gold quality
adrenal gland	UBERON:0002369	72.67	gold quality
squamous epithelium	UBERON:0006914	72.62	gold quality
pancreas	UBERON:0001264	72.11	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.85
E-MTAB-7303	no	677.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, EAF2, EGR1, FOXN1, FOXO1, MTA3, MYC, OTX2, PAX2, RUNX3, SOX11, SRY, TCF4, TP53, TP63, TP73, WT1, ZIC1

miRNA regulators (miRDB)

147 targeting WNT4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 40)

• WNT-4 protein is expressed in the developing nephron during morphogenetic period of the kidney. (PMID:12768078)
• Down-regulation of Wnt-4 and up-regulation of Wnt-5a are possible markers of the malignant phenotype of human squamous cell carcinoma. (PMID:12841867)
• overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy (PMID:12949260)
• matrilysin may have a role in renal tubular injury and progression of tubulointerstitial fibrosis, and Wnt4 may regulate matrilysin expression in the kidney (PMID:15149334)
• Their different spatial expression patterns suggest that Wnt4 and Wnt5a proteins are not functionally linked to type II collagen and type X collagen synthesis in in vitro chondrogenic models of mesenchyme stem cells (PMID:15389636)
• sequencing of all five exons of WNT-4 demonstrated no mutant alleles in any of 8 46,XX true hermaphrodites. The possibility of the existence of causative mutations in the untranslated regions of WNT-4, or within introns cannot be ruled out. (PMID:15589122)
• It is thus likely that both RE1 and RE2 are necessary in rendering p63/p73-specific activation of the WNT4 promoter. (PMID:16343436)
• Bone morphogenetic protein-2 modulates Wnt and frizzled expression and enhances the canonical pathway of Wnt signaling in normal keratinocytes (PMID:16442268)
• These data show that DKK3 and WNT4 have multiple actions on steroidogenesis in adrenocortical cells, including effects on overall steroidogenesis (aldosterone and cortisol biosynthesis) and distinct effects on steroidogenic enzyme mRNA levels. (PMID:16981135)
• The activation of p38 was dependent on Axin and was required for the enhancement of mesenchymal stem cells differentiation by Wnt-4. (PMID:17720811)
• Molecular analysis of the WNT4 gene in 6 patients with Mayer-Rokitansky-Kuster-Hauser syndrome without androgen excess excluded this gene as a major cause of this syndrome, regardless of the subtype. (PMID:18001722)
• Together with previous observations in animal models, the present data attribute a pivotal role to WNT4 signaling during organogenesis in humans. (PMID:18179883)
• WNT4 is involved in the regulation of mullerian duct development and ovarian androgen biosynthesis. WNT4 may also contribute to human follicle development and/or maintenance. (PMID:18182450)
• Wnt4 gene, a member of the Wnt-beta-catenin pathway, was identified as a target gene of MM-1. (PMID:18281035)
• The abundant WNT-4 mRNA expression in Conn’s adenomas and its hormonal regulation in adrenocortical cells suggest a role for WNT-4 in human adrenocortical function. (PMID:18553255)
• These results suggested that activation of Wnt4/Fzd6 signaling through a “beta-catenin-independent” pathway played a role in proliferation and survival of the pituitary adenoma cells. (PMID:19034702)
• Mutations in the coding sequence of WNT4, WNT5A, WNT7A, and WNT9B are not responsible for the Mayer-Rokitansky-Kuster-Hauser syndrome. (PMID:19171330)
• RNA samples from 21 neuroblastoma showed a highly significant FZD1 and/or MDR1 overexpression after treatment, underlining a role for FZD1-mediated Wnt/beta-catenin pathway in clinical chemoresistance. (PMID:19421142)
• Wnt 4a gene encodes a growth factor that participates in the formation of the kidney, adrenal, mammary gland, pituitary, and female reproductive tract. Wnt4 is required for the initial steps of the formation of Mullerian ducts. (PMID:19849868)
• Results demonstrated significant up-regulation of WNT-3, WNT-4, WNT-5B, WNT-7B, WNT-9A, WNT-10A, and WNT-16B in patients with CLL compared to normal subjects. (PMID:19863181)
• The current results support a view that WNT4 may have a role in oocyte selection and follicle formation and maturation in human ovaries. (PMID:19962424)
• at least 1 cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a loss of function mutation of the Wnt4 (wingless-type MMTV integration site family member 4) gene. (PMID:20060343)
• Findings provide the first convincing line of evidence that EAF and Wnt4 form an auto-regulatory negative feedback loop in vivo. (PMID:20161747)
• The age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2alpha expression, was investigated in thymic epithelial cells. (PMID:20502698)
• Wnt4 is specifically involved in joint development. (PMID:20709709)
• These observations highlight the distinct roles of WNT11 and WNT4 during the early stages of retinoic acid-induced neuronal differentiation. (PMID:21280163)
• Report a new WNT4 gene mutation in atypical Mayer-Rokitansky-Kuster-Hauser syndrome. (PMID:21377155)
• Possible role of WNT4 in Han Chinese women with premature ovarian failure. (PMID:21624127)
• Wnt/beta-catenin pathway forms a negative feedback loop during TGF-beta1 induced human normal skin fibroblast-to-myofibroblast transition (PMID:22041457)
• Mutations in WNT4 are not responsible for Mullerian duct abnormalities in Chinese women. (PMID:22503279)
• Mutations in the WNT4 gene is not associated with premature ovarian failure. (PMID:22951804)
• Recent developments have demonstrated that ovarian development is an active process (rather than a default process); ovarian development/function requires expression of WNT4, RSPO1, and FOXL2. [REVIEW] (PMID:23044875)
• We confirm WNT4, CDKN2BAS and FN1 as the first identified common loci for endometriosis. (PMID:23142796)
• Studies uncovered a linear pathway involving BMP2, WNT4/beta-catenin, and Forkhead box protein O1 that operates in human endometrium to critically control decidualization. (PMID:23142810)
• Analysis of bronchial biopsy samples shows a very strong correlation between Wnt4 and interleukin (IL)8 gene expression, suggesting a role for Wnt4 in chronic lung inflammation. (PMID:23463699)
• heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia. (PMID:23520208)
• State anxiety assessed two months before the examination was positively and negatively correlated with miR-16 and its target WNT4 mRNA levels, respectively. (PMID:24130753)
• These data indicate that Wnt4 signaling is deregulated in most pituitary adenomas and its excessive activation may inhibit pituitary tumor invasion. (PMID:24200887)
• The WNT4 ligand plays a role in regulating the cell growth of leukemia-derived cells by arresting cells in the G1 cell cycle phase. (PMID:24274766)
• We report an adolescent girl with the cardinal features of MURCS association, obesity, and clinical findings of hyperandrogenism who did not show any exonic mutation of the WNT4 gene (PMID:24356390)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	wnt4	ENSDARG00000071208
mus_musculus	Wnt4	ENSMUSG00000036856
rattus_norvegicus	Wnt4	ENSRNOG00000013166
drosophila_melanogaster	Wnt2	FBGN0004360
drosophila_melanogaster	Wnt5	FBGN0010194
drosophila_melanogaster	Wnt10	FBGN0031903
caenorhabditis_elegans		WBGENE00000857
caenorhabditis_elegans		WBGENE00000858
caenorhabditis_elegans	lin-44	WBGENE00003029

Paralogs (18): WNT16 (ENSG00000002745), WNT8A (ENSG00000061492), WNT8B (ENSG00000075290), WNT11 (ENSG00000085741), WNT2 (ENSG00000105989), WNT3 (ENSG00000108379), WNT5B (ENSG00000111186), WNT5A (ENSG00000114251), WNT6 (ENSG00000115596), WNT1 (ENSG00000125084), WNT2B (ENSG00000134245), WNT10A (ENSG00000135925), WNT9A (ENSG00000143816), WNT3A (ENSG00000154342), WNT7A (ENSG00000154764), WNT9B (ENSG00000158955), WNT10B (ENSG00000169884), WNT7B (ENSG00000188064)

Protein

Protein identifiers

Protein Wnt-4 — P56705 (reviewed: P56705)

All UniProt accessions (3): B1AJZ6, P56705, H0Y663

UniProt curated annotations — full annotation on UniProt →

Function. Ligand for members of the frizzled family of seven transmembrane receptors. Plays an important role in the embryonic development of the urogenital tract and the lung. Required for normal mesenchyme to epithelium transition during embryonic kidney development. Required for the formation of early epithelial renal vesicles during kidney development. Required for normal formation of the Mullerian duct in females, and normal levels of oocytes in the ovaries. Required for normal down-regulation of 3 beta-hydroxysteroid dehydrogenase in the ovary. Required for normal lung development and for normal patterning of trachael cartilage rings.

Subunit / interactions. Interacts with PORCN. Interacts with PKD1.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Post-translational modifications. Palmitoleoylation is required for efficient binding to frizzled receptors. Depalmitoleoylation leads to Wnt signaling pathway inhibition.

Disease relevance. 46,XX sex reversal with dysgenesis of kidneys, adrenals, and lungs (SERKAL) [MIM:611812] A disease characterized by the association of female-to-male sex reversal with dysgenesis of kidneys, adrenals, and lungs. The disease is caused by variants affecting the gene represented in this entry. Mullerian aplasia and hyperandrogenism (MULLAPL) [MIM:158330] A disorder of sex development. Affected females manifest dysgenesis of Mullerian duct derivatives absent or rudimentary uterus and vagina, functional ovaries, primary amenorrhea, hyperandrogenism and hirsutism. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Wnt family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56705-1	1	yes
P56705-2	2

RefSeq proteins (1): NP_110388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005817	Wnt	Family
IPR009142	Wnt4	Family
IPR018161	Wnt_CS	Conserved_site
IPR043158	Wnt_C	Homologous_superfamily

Pfam: PF00110

UniProt features (24 total): disulfide bond 11, sequence variant 5, sequence conflict 2, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56705-F1	91.41	0.82

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 212

Disulfide bonds (11): 280–311, 296–306, 310–350, 326–341, 328–338, 333–334, 78–89, 128–136, 138–155, 206–220, 208–215

Glycosylation sites (2): 88, 297

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-3238698	WNT ligand biogenesis and trafficking
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-3772470	Negative regulation of TCF-dependent signaling by WNT ligand antagonists
R-HSA-4086400	PCP/CE pathway
R-HSA-9831926	Nephron development
R-HSA-9690406	Transcriptional regulation of testis differentiation

MSigDB gene sets: 681 (showing top): AHRARNT_01, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, CREL_01, MODULE_92, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_GLAND_MORPHOGENESIS, HNF3ALPHA_Q6, GOBP_METANEPHROS_DEVELOPMENT

GO Biological Process (74): branching involved in ureteric bud morphogenesis (GO:0001658), kidney development (GO:0001822), epithelial to mesenchymal transition (GO:0001837), embryonic epithelial tube formation (GO:0001838), liver development (GO:0001889), fibroblast growth factor receptor signaling pathway (GO:0008543), male gonad development (GO:0008584), female gonad development (GO:0008585), cellular response to starvation (GO:0009267), negative regulation of gene expression (GO:0010629), negative regulation of steroid biosynthetic process (GO:0010894), regulation of cell-cell adhesion (GO:0022407), neuron differentiation (GO:0030182), female sex determination (GO:0030237), adrenal gland development (GO:0030325), negative regulation of cell migration (GO:0030336), positive regulation of bone mineralization (GO:0030501), positive regulation of aldosterone biosynthetic process (GO:0032349), positive regulation of collagen biosynthetic process (GO:0032967), immature T cell proliferation in thymus (GO:0033080), non-canonical Wnt signaling pathway (GO:0035567), negative regulation of fibroblast growth factor receptor signaling pathway (GO:0040037), hormone metabolic process (GO:0042445), positive regulation of MAPK cascade (GO:0043410), cell fate commitment (GO:0045165), negative regulation of cell differentiation (GO:0045596), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of meiotic nuclear division (GO:0045836), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), negative regulation of Ras protein signal transduction (GO:0046580), oocyte development (GO:0048599), smooth muscle cell differentiation (GO:0051145), positive regulation of stress fiber assembly (GO:0051496), positive regulation of focal adhesion assembly (GO:0051894), Sertoli cell differentiation (GO:0060008), canonical Wnt signaling pathway (GO:0060070), somatotropin secreting cell differentiation (GO:0060126), thyroid-stimulating hormone-secreting cell differentiation (GO:0060129), mesenchymal to epithelial transition (GO:0060231)

GO Molecular Function (5): transcription corepressor activity (GO:0003714), frizzled binding (GO:0005109), cytokine activity (GO:0005125), receptor ligand activity (GO:0048018), signaling receptor binding (GO:0005102)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), cell surface (GO:0009986), endocytic vesicle membrane (GO:0030666), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by WNT	2
GPCR ligand binding	1
TCF dependent signaling in response to WNT	1
Beta-catenin independent WNT signaling	1
Kidney development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
gland development	2
gonad development	2
intracellular organelle lumen	2
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
animal organ development	1
renal system development	1
mesenchymal cell differentiation	1
morphogenesis of embryonic epithelium	1
epithelial tube formation	1
hepaticobiliary system development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
development of primary male sexual characteristics	1
development of primary female sexual characteristics	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
steroid biosynthetic process	1
negative regulation of steroid metabolic process	1
regulation of steroid biosynthetic process	1
negative regulation of lipid biosynthetic process	1
regulation of cell adhesion	1
cell-cell adhesion	1
cell differentiation	1
generation of neurons	1
multicellular organism development	1
sex determination	1
endocrine system development	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1

Protein interactions and networks

STRING

2276 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WNT4	FZD6	O60353	943
WNT4	RSPO1	Q2MKA7	920
WNT4	FZD2	Q14332	914
WNT4	FZD4	Q9ULV1	873
WNT4	CTNNB1	P35222	872
WNT4	FZD5	Q13467	861
WNT4	FZD9	O00144	858
WNT4	FZD8	Q9H461	858
WNT4	FZD3	Q9NPG1	855
WNT4	RYK	P34925	852
WNT4	LRP5	O75197	830
WNT4	FZD1	Q9UP38	816
WNT4	SRY	Q05066	808
WNT4	FZD7	O75084	798
WNT4	VANGL2	Q9ULK5	781

IntAct

9 interactions, top by confidence:

A	B	Type	Score
WNT4	TOMM40	psi-mi:“MI:0914”(association)	0.530
TMEM80	WNT4	psi-mi:“MI:0915”(physical association)	0.490
P2RX4	WNT4	psi-mi:“MI:0915”(physical association)	0.370
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
WNT4	HLA-B	psi-mi:“MI:0914”(association)	0.350

BioGRID (62): WLS (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), CAMK2D (Affinity Capture-MS), WNT7B (Affinity Capture-MS), BORA (Affinity Capture-MS), PASK (Affinity Capture-MS), VWA9 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), RNF40 (Affinity Capture-MS), MTCH2 (Affinity Capture-MS), WNT5A (Affinity Capture-MS), CRELD2 (Affinity Capture-MS), CBWD3 (Affinity Capture-MS), ITPA (Affinity Capture-MS), FBLN1 (Affinity Capture-MS)

ESM2 similar proteins: B2GUT4, O00744, O13267, O42237, O73864, O96014, P04426, P04628, P09615, P10108, P10600, P17125, P21551, P22724, P22725, P22726, P24257, P31286, P33945, P41221, P43446, P47793, P48614, P48615, P49337, P49338, P49339, P49340, P49893, P51891, P56705, P70275, P87387, Q06442, Q06443, Q07258, Q27Q52, Q28J82, Q4VC17, Q5NVK2

Diamond homologs: A0M8S1, A0M8T2, A1X153, A4D7S0, B2GUT4, O00755, O13267, O15978, O42122, O70283, P04426, P04628, P09544, P09615, P10108, P17553, P21551, P21552, P22724, P22725, P22726, P22727, P24257, P24383, P27467, P28047, P28465, P31285, P31286, P33945, P34888, P34889, P41221, P43446, P47793, P49337, P49338, P49339, P49340, P49893

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
SFRP1	down-regulates	WNT4	binding
WNT4	up-regulates	LRP5	binding
WNT4	up-regulates	LRP6	binding
WNT4	up-regulates	MYF5
WNT4	up-regulates	MYOD1
SOSTDC1	“down-regulates activity”	WNT4

Disease & clinical

Clinical variants and AI predictions

ClinVar

173 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	97
Likely benign	49
Benign	11

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
3897943	NM_030761.5(WNT4):c.872C>G (p.Thr291Arg)	Pathogenic
6308	NM_030761.5(WNT4):c.647A>G (p.Glu216Gly)	Pathogenic
6309	NM_030761.5(WNT4):c.341C>T (p.Ala114Val)	Pathogenic
6310	NM_030761.5(WNT4):c.247C>T (p.Arg83Trp)	Pathogenic
6311	NM_030761.5(WNT4):c.35T>C (p.Leu12Pro)	Pathogenic

SpliceAI

964 predictions. Top by Δscore:

Variant	Effect	Δscore
1:22121207:CTA:C	donor_loss	1.0000
1:22121208:TACC:T	donor_loss	1.0000
1:22121209:AC:A	donor_loss	1.0000
1:22121210:CC:C	donor_loss	1.0000
1:22121213:T:A	donor_gain	1.0000
1:22121359:G:C	acceptor_gain	1.0000
1:22121359:G:GC	acceptor_gain	1.0000
1:22121361:G:C	acceptor_gain	1.0000
1:22121361:G:GC	acceptor_gain	1.0000
1:22121364:G:C	acceptor_gain	1.0000
1:22121364:G:GC	acceptor_gain	1.0000
1:22121369:C:CT	acceptor_gain	1.0000
1:22121443:AC:A	donor_gain	1.0000
1:22121444:CC:C	donor_gain	1.0000
1:22142842:TTACA:T	donor_loss	1.0000
1:22142844:A:AC	donor_gain	1.0000
1:22142844:ACAG:A	donor_gain	1.0000
1:22142844:ACAGC:A	donor_gain	1.0000
1:22142845:C:CT	donor_gain	1.0000
1:22142845:CA:C	donor_gain	1.0000
1:22142845:CAG:C	donor_gain	1.0000
1:22142845:CAGC:C	donor_gain	1.0000
1:22142845:CAGCC:C	donor_gain	1.0000
1:22120514:TGGC:T	acceptor_gain	0.9900
1:22120514:TGGCC:T	acceptor_loss	0.9900
1:22120515:GGCCT:G	acceptor_loss	0.9900
1:22120517:CCT:C	acceptor_loss	0.9900
1:22120518:C:CC	acceptor_gain	0.9900
1:22120518:CTGT:C	acceptor_loss	0.9900
1:22120519:T:C	acceptor_loss	0.9900

AlphaMissense

2279 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:22120110:C:A	W332C	1.000
1:22120110:C:G	W332C	1.000
1:22120116:G:C	F330L	1.000
1:22120116:G:T	F330L	1.000
1:22120117:A:C	F330C	1.000
1:22120117:A:G	F330S	1.000
1:22120118:A:G	F330L	1.000
1:22120218:G:C	C296W	1.000
1:22120219:C:G	C296S	1.000
1:22120219:C:T	C296Y	1.000
1:22120220:A:T	C296S	1.000
1:22120267:C:G	C280S	1.000
1:22120267:C:T	C280Y	1.000
1:22120268:A:T	C280S	1.000
1:22120269:G:C	F279L	1.000
1:22120269:G:T	F279L	1.000
1:22120270:A:C	F279C	1.000
1:22120271:A:G	F279L	1.000
1:22120297:A:G	L270P	1.000
1:22120392:A:C	F238L	1.000
1:22120392:A:T	F238L	1.000
1:22120394:A:G	F238L	1.000
1:22120401:C:A	K235N	1.000
1:22120401:C:G	K235N	1.000
1:22120443:C:A	W221C	1.000
1:22120443:C:G	W221C	1.000
1:22120446:G:C	C220W	1.000
1:22120447:C:G	C220S	1.000
1:22120447:C:T	C220Y	1.000
1:22120448:A:G	C220R	1.000

dbSNP variants (sampled 300 via entrez): RS1000018283 (1:22134400 ACCATACCCC>A), RS1000045185 (1:22124145 G>A), RS1000065314 (1:22131784 T>C), RS1000194437 (1:22132929 T>C), RS1000698285 (1:22141345 C>T), RS1000859162 (1:22130115 C>A), RS1000915798 (1:22119685 C>T), RS1000958062 (1:22128782 C>T), RS1001030661 (1:22122530 A>C), RS1001536216 (1:22123010 G>A), RS1001575079 (1:22116855 G>A), RS1001753547 (1:22141474 T>G), RS1001785287 (1:22118203 G>A,T), RS1001786820 (1:22122795 C>T), RS1001951085 (1:22134959 C>T)

Disease associations

OMIM: gene MIM:603490 | disease phenotypes: MIM:158330, MIM:611812

GenCC curated gene-disease

Disease	Classification	Inheritance
mullerian aplasia and hyperandrogenism	Strong	Autosomal dominant
SERKAL syndrome	Strong	Autosomal recessive

Mondo (3): mullerian aplasia and hyperandrogenism (MONDO:0008019), SERKAL syndrome (MONDO:0012734), Mayer-Rokitansky-Kuster-Hauser syndrome (MONDO:0017771)

Orphanet (4): SERKAL syndrome (Orphanet:139466), Müllerian aplasia and hyperandrogenism (Orphanet:247768), Mayer-Rokitansky-Küster-Hauser syndrome type 1 (Orphanet:247775), Mayer-Rokitansky-Küster-Hauser syndrome (Orphanet:3109)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000027	Azoospermia
HP:0000036	Abnormal penis morphology
HP:0000047	Hypospadias
HP:0000086	Ectopic kidney
HP:0000104	Renal agenesis
HP:0000110	Renal dysplasia
HP:0000122	Unilateral renal agenesis
HP:0000137	Abnormality of the ovary
HP:0000142	Abnormal vagina morphology
HP:0000151	Aplasia of the uterus
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000322	Short philtrum
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000470	Short neck
HP:0000574	Thick eyebrow
HP:0000664	Synophrys
HP:0000772	Abnormal rib morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000786	Primary amenorrhea
HP:0000811	Abnormal external genitalia morphology
HP:0000813	Bicornuate uterus
HP:0000834	Abnormality of the adrenal glands
HP:0000914	Shield chest
HP:0001007	Hirsutism

GWAS associations

78 associations (top):

Study	Trait	p-value
GCST000721_2	Endometriosis	2.000000e-06
GCST001144_1	Dupuytren’s disease	3.000000e-09
GCST001482_21	Lumbar spine bone mineral density	1.000000e-10
GCST001720_1	Endometriosis	3.000000e-11
GCST001762_230	Obesity-related traits	9.000000e-06
GCST001894_5	Endometriosis	7.000000e-09
GCST001894_6	Endometriosis	6.000000e-06
GCST001894_7	Endometriosis	8.000000e-07
GCST001894_8	Endometriosis	3.000000e-09
GCST002492_8	Bone mineral density (paediatric, lower limb)	3.000000e-08
GCST002492_9	Bone mineral density (paediatric, lower limb)	6.000000e-08
GCST002493_17	Bone mineral density (paediatric, skull)	1.000000e-10
GCST002493_18	Bone mineral density (paediatric, skull)	2.000000e-12
GCST002494_1	Bone mineral density (paediatric, total body less head)	7.000000e-10
GCST002494_10	Bone mineral density (paediatric, total body less head)	4.000000e-09
GCST002496_5	Bone mineral density (paediatric, upper limb)	3.000000e-07
GCST002496_9	Bone mineral density (paediatric, upper limb)	1.000000e-08
GCST002748_12	Epithelial ovarian cancer	2.000000e-08
GCST002748_17	Epithelial ovarian cancer	8.000000e-08
GCST002919_1	Colorectal cancer	1.000000e-08
GCST003518_28	Daytime sleep phenotypes	3.000000e-06
GCST004067_109	Hip circumference adjusted for BMI	3.000000e-08
GCST004067_147	Hip circumference adjusted for BMI	3.000000e-06
GCST004368_3	Endometriosis	6.000000e-07
GCST004370_7	Deep ovarian and/or rectovaginal disease with dense adhesions	6.000000e-07
GCST004549_11	Endometriosis	9.000000e-17
GCST004549_28	Endometriosis	1.000000e-12
GCST004549_8	Endometriosis	2.000000e-06
GCST004771_12	TB-LM or TBLH-BMD (pleiotropy)	6.000000e-09
GCST004772_1	Bone mineral density (paediatric, total body less head)	1.000000e-08

EFO canonical traits (21, from GWAS)

EFO ID	Trait name
EFO:0004229	Dupuytren Contracture
EFO:0004736	aspartate aminotransferase measurement
EFO:0007828	daytime rest measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004995	lean body mass
EFO:0005112	gestational age
EFO:0005939	parental genotype effect measurement
EFO:0004344	birth weight
EFO:0007702	hip bone mineral density
EFO:0009270	heel bone mineral density
EFO:0006335	systolic blood pressure
EFO:0007620	volumetric bone mineral density
EFO:0004337	intelligence
EFO:0004508	spine bone size
EFO:0004314	forced expiratory volume
EFO:0010114	citrate measurement
EFO:0007710	cognitive decline measurement
EFO:0004459	ferritin measurement
EFO:0004530	triglyceride measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004980	appendicular lean mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567186	Mullerian Aplasia and Hyperandrogenism (supp.)
C567517	Sex Reversal, Female, With Dysgenesis Of Kidneys, Adrenals, And Lungs (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	6
trichostatin A	increases expression, affects cotreatment	3
belinostat	increases expression, affects cotreatment	3
Estradiol	affects cotreatment, decreases expression, increases expression, increases reaction	3
sodium arsenite	increases expression	2
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Cisplatin	affects cotreatment, increases expression	2
Nickel	decreases expression	2
8-Bromo Cyclic Adenosine Monophosphate	increases expression, increases reaction, decreases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
abemaciclib	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
TL8-506	affects cotreatment, increases expression	1
methyleugenol	increases expression	1
sodium arsenate	increases abundance, decreases expression	1
arsenite	decreases expression	1
afimoxifene	increases expression	1
cobaltous chloride	affects cotreatment, decreases expression	1
beryllium sulfate	increases expression	1
perfluorooctanoic acid	increases expression	1
tri-o-cresyl phosphate	decreases expression	1
lead chloride	decreases expression, affects cotreatment	1
hydroquinone	decreases expression	1
cadmium sulfate	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
picene	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0T2	Ubigene HeLa WNT4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

14 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03277430	PHASE3	UNKNOWN	Uterus Transplantation From Live Donors and From Deceased Donors - Clinical Study
NCT01911884	Not specified	COMPLETED	Assessment of Quality of Global and Sexual Life and Impact of Surgical and Non Surgical Vaginal Aplasia in Patients With a Rokitansky Syndrome
NCT02967822	Not specified	RECRUITING	Molecular Genetic Study of Mayer-Rokitansky-Kuster-Hauser Syndrome
NCT03252795	Not specified	RECRUITING	Uterus Transplantation From a Multi-organ Donor
NCT03307356	Not specified	ACTIVE_NOT_RECRUITING	The University of Pennsylvania Uterus Transplant for Uterine Factor Infertility Trial
NCT03689842	Not specified	RECRUITING	Feasibility Study of Uterine Transplantation From Living Donors in Terms of Efficacy and Safety in Patients With Mayer-Rokitansky-Küster-Hauser Syndrome (MRKH)
NCT04314869	Not specified	UNKNOWN	Uterus Transplantation Procedure From a Live Donor
NCT04923217	Not specified	COMPLETED	Quality of Life and Sexual Function in Vaginal Aplasia Patients After Davydov Procedure
NCT05263076	Not specified	RECRUITING	Uterine Transplant for Women With Absolute Uterine Factor Infertility (AUFI)
NCT05415540	Not specified	COMPLETED	Evolution of the Quality of Life and Experience of Young Women With Utero-vaginal Aplasia (MRKHPSY)
NCT05925361	Not specified	UNKNOWN	Peritoneum Vaginoplasty; Implementation According to IDEAL Framework
NCT06508151	Not specified	NOT_YET_RECRUITING	Neovaginoplasty Using Photoinduced-imine-crosslink Hydrogel in MRKH Patients
NCT07186764	Not specified	RECRUITING	Evaluation of the Quality of Life and Gynecological Follow-up of Patients Treated for Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome
NCT07321782	Not specified	NOT_YET_RECRUITING	Clinical and Imaging Features in MRKH Syndrome