WNT9A

Summary

WNT9A (Wnt family member 9A, HGNC:12778) is a protein-coding gene on chromosome 1q42.13, encoding Protein Wnt-9a (O14904). Ligand for members of the frizzled family of seven transmembrane receptors.

The WNT gene family consists of structurally related genes that 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. It is expressed in gastric cancer cell lines. The protein encoded by this gene shows 75% amino acid identity to chicken Wnt14, which has been shown to play a central role in initiating synovial joint formation in the chick limb. This gene is clustered with another family member, WNT3A, in the chromosome 1q42 region.

Source: NCBI Gene 7483 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 68 total
• MANE Select transcript: NM_003395

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12778
Approved symbol	WNT9A
Name	Wnt family member 9A
Location	1q42.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143816
Ensembl biotype	protein_coding
OMIM	602863
Entrez	7483

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000272164

RefSeq mRNA: 1 — MANE Select: NM_003395 NM_003395

CCDS: CCDS31045

Canonical transcript exons

ENST00000272164 — 4 exons

Exon	Start	End
ENSE00000962105	227918656	227922000
ENSE00001442545	227924138	227924400
ENSE00001871974	227947793	227947932
ENSE00003523614	227925263	227925519

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 92.33.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3015 / max 112.2252, expressed in 768 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17806	2.3015	768

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	92.33	gold quality
oocyte	CL:0000023	87.59	gold quality
gastrocnemius	UBERON:0001388	86.39	gold quality
muscle of leg	UBERON:0001383	85.39	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.30	gold quality
tendon of biceps brachii	UBERON:0008188	85.28	silver quality
epithelial cell of pancreas	CL:0000083	83.78	gold quality
parotid gland	UBERON:0001831	83.78	silver quality
muscle layer of sigmoid colon	UBERON:0035805	83.43	gold quality
secondary oocyte	CL:0000655	83.12	gold quality
tibialis anterior	UBERON:0001385	81.64	silver quality
mucosa of paranasal sinus	UBERON:0005030	81.12	gold quality
nasal cavity epithelium	UBERON:0005384	81.05	silver quality
quadriceps femoris	UBERON:0001377	80.71	silver quality
cartilage tissue	UBERON:0002418	80.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	80.28	gold quality
lower esophagus	UBERON:0013473	80.24	gold quality
vastus lateralis	UBERON:0001379	80.14	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	78.03	gold quality
right ovary	UBERON:0002118	77.41	gold quality
left ovary	UBERON:0002119	77.20	gold quality
heart right ventricle	UBERON:0002080	76.58	silver quality
lower esophagus mucosa	UBERON:0035834	76.36	gold quality
skeletal muscle tissue	UBERON:0001134	76.21	gold quality
esophagus	UBERON:0001043	76.03	gold quality
deltoid	UBERON:0001476	76.02	silver quality
bronchial epithelial cell	CL:0002328	76.00	gold quality
pancreatic ductal cell	CL:0002079	75.96	silver quality
left ventricle myocardium	UBERON:0006566	75.30	silver quality
bronchus	UBERON:0002185	75.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, SP1

Literature-anchored findings (GeneRIF, showing 19)

• The data indicate a global role of eIF4AIII in gene expression, which would be independent of Y14 and MAGO, splicing, and of the exon junction complex, as currently understood. (PMID:27879206)
• Found clustered with WNT3A on 1q42. . (PMID:11836627)
• 5’-flanking promoter region was significantly divergent between human WNT9A and rodent Wnt9a genes. (PMID:15809769)
• These results suggests the expression level of human Wnt9a in MCF-7 that breast cancer may play a role in adjusting the rate of cellular proliferation. (PMID:17351820)
• cDNA gene expression array of Wnt signaling pathway target genes demonstrated significant changes, including 4.5-fold induction of Wnt 9A and suppression of Dickkopf 3 and RHOU genes. (PMID:17429723)
• 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)
• Using DirectDNA sequencing analysis, we detected ATBF1, CYLD, PARK2 and WNT9A mutations in stomach and colorectal cancers (PMID:20854080)
• Transgenic wnt9a is required for palatal extension wherein the chondrocytes form a proliferative front, undergo morphological change and intercalate to form the ethmoid plate. (PMID:23154410)
• These studies reveal how carrageenan exposure can lead to transcriptional events in colonic epithelial cells through decline in arylsulfatase B activity, with subsequent impact on C4S, galectin-3, Sp1, and Wnt9A (PMID:24778176)
• Silencing Wnt9A increased the expression of CHST11 in the colonic epithelial cells, and chromatin immunoprecipitation assay demonstrated enhancing effects of Wnt9A siRNA and exogenous BMP4 on the CHST11 promoter (PMID:25511584)
• expression is enhanced in idiopathic carpal tunnel syndrome (PMID:26174360)
• Inhibition of WNT signaling by the PORCN inhibitor WNT974 reduced metastatic spread of UM-SCC cells, especially in UM-SCCs with Notch1 deficiency. (PMID:27117272)
• This manipulation increased one type of sensory hair cell (tall HCs) at the expense of another (short HCs) that is usually located furthest from the Wnt9a source. The extraneous tall HCs that replaced short HCs showed some physiological properties and neuronal connections consistent with a fate switch. (PMID:28821654)
• Compared with normal tubular cells, tubular cells of humans with a variety of nephropathies expressed high levels of Wnt9a that colocalized with p16(INK4A). Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16(INK4A).In a proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a upregulated p16(INK4A). (PMID:29440280)
• We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction (PMID:31110287)
• Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify WNT9A as novel osteoarthritis gene. (PMID:33055079)
• Loss of the WNT9a ligand aggravates the rheumatoid arthritis-like symptoms in hTNF transgenic mice. (PMID:33990546)
• WNT9A Affects Late-Onset Acute Respiratory Distress Syndrome and 28-Day Survival: Evidence from a Three-Step Multiomics Study. (PMID:37094100)
• Genetic polymorphism of WNT9A is functionally associated with thumb osteoarthritis in the Chinese population. (PMID:38287451)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	wnt9a	ENSDARG00000063437
mus_musculus	Wnt9a	ENSMUSG00000000126
rattus_norvegicus	Wnt9a	ENSRNOG00000003066
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), WNT3A (ENSG00000154342), WNT7A (ENSG00000154764), WNT9B (ENSG00000158955), WNT4 (ENSG00000162552), WNT10B (ENSG00000169884), WNT7B (ENSG00000188064)

Protein

Protein identifiers

Protein Wnt-9a — O14904 (reviewed: O14904)

Alternative names: Protein Wnt-14

All UniProt accessions (2): O14904, D9ZGG3

UniProt curated annotations — full annotation on UniProt →

Function. Ligand for members of the frizzled family of seven transmembrane receptors. Functions in the canonical Wnt/beta-catenin signaling pathway. Required for normal timing of IHH expression during embryonic bone development, normal chondrocyte maturation and for normal bone mineralization during embryonic bone development. Plays a redundant role in maintaining joint integrity.

Subunit / interactions. Forms a soluble 1:1 complex with AFM; this prevents oligomerization and is required for prolonged biological activity. The complex with AFM may represent the physiological form in body fluids.

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.

Similarity. Belongs to the Wnt family.

RefSeq proteins (1): NP_003386* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005817	Wnt	Family
IPR013303	Wnt9a	Family
IPR018161	Wnt_CS	Conserved_site
IPR043158	Wnt_C	Homologous_superfamily

Pfam: PF00110

UniProt features (17 total): disulfide bond 11, signal peptide 1, chain 1, sequence variant 1, region of interest 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14904-F1	83.18	0.60

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): 221

Disulfide bonds (11): 299–324, 313–319, 323–363, 339–354, 341–351, 346–347, 93–104, 141–149, 151–168, 215–229, 217–224

Glycosylation sites (1): 103

Function

Pathways and Gene Ontology

Reactome pathways

4 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

MSigDB gene sets: 142 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_CARTILAGE_DEVELOPMENT, KEGG_HEDGEHOG_SIGNALING_PATHWAY, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, AP4_Q6, GOBP_NEUROGENESIS, LHX3_01, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, EVI1_05, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (11): negative regulation of cell population proliferation (GO:0008285), neuron differentiation (GO:0030182), negative regulation of chondrocyte differentiation (GO:0032331), cell fate commitment (GO:0045165), canonical Wnt signaling pathway (GO:0060070), iris morphogenesis (GO:0061072), cornea development in camera-type eye (GO:0061303), cellular response to retinoic acid (GO:0071300), embryonic skeletal joint development (GO:0072498), multicellular organism development (GO:0007275), Wnt signaling pathway (GO:0016055)

GO Molecular Function (5): frizzled binding (GO:0005109), cytokine activity (GO:0005125), receptor ligand activity (GO:0048018), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by WNT	2
GPCR ligand binding	1
TCF dependent signaling in response to WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
anatomical structure development	2
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
generation of neurons	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
cellular developmental process	1
Wnt signaling pathway	1
anatomical structure morphogenesis	1
camera-type eye morphogenesis	1
camera-type eye development	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
embryonic skeletal system development	1
multicellular organismal process	1
cell surface receptor signaling pathway	1
G protein-coupled receptor binding	1
receptor ligand activity	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
protein binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WNT9A	CTNNB1	P35222	742
WNT9A	RORA	P35397	728
WNT9A	LRP5	O75197	694
WNT9A	FZD1	Q9UP38	604
WNT9A	GDF5	P43026	598
WNT9A	AXIN2	Q9Y2T1	590
WNT9A	FZD9	O00144	576
WNT9A	TCF7	P36402	563
WNT9A	DKK1	O94907	554
WNT9A	FZD2	Q14332	545
WNT9A	FRZB	Q92765	545
WNT9A	FZD6	O60353	544
WNT9A	FZD8	Q9H461	544
WNT9A	FZD7	O75084	542
WNT9A	MUSK	O15146	540

IntAct

7 interactions, top by confidence:

A	B	Type	Score
WNT9A	ZBTB14	psi-mi:“MI:0915”(physical association)	0.560
WNT9A	AFM	psi-mi:“MI:0915”(physical association)	0.400
WNT9A	WLS	psi-mi:“MI:0915”(physical association)	0.400
WNT9A	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
WNT9A	ZBTB14	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): ZBTB14 (Two-hybrid), WNT9A (Co-localization)

ESM2 similar proteins: A4D7S0, A8XEH1, O00755, O14904, O15978, O42280, P09544, P24383, P28026, P28047, P28107, P28111, P28130, P28144, P28465, P31291, P34888, P34889, P51028, P51029, P51030, P56706, Q07DW8, Q07DX7, Q07DY7, Q09YI4, Q09YJ6, Q10459, Q1KYK4, Q1KYK5, Q1KYK6, Q1KYK7, Q1KYK9, Q1KYL1, Q1KYL3, Q27886, Q2IBB0, Q2IBE2, Q2QL76, Q2QL96

Diamond homologs: A0M8S1, A0M8T2, A1X153, A4D7S0, O00744, O00755, O13267, O14904, O14905, O15978, O35468, O42280, O70283, P04426, P04628, P09544, P10108, P21551, P21552, P22724, P22725, P22726, P22727, P24257, P24383, P27467, P28047, P28465, P31286, P33945, P40589, P41221, P43446, P47793, P48614, P49337, P49338, P49339, P49340, P51029

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
WNT9A	up-regulates	FZD3	binding
WNT9A	up-regulates	LRP5	binding
WNT9A	up-regulates	LRP6	binding
WNT9A	up-regulates	CHRNA1	binding
WNT9A	up-regulates	MUSK	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

947 predictions. Top by Δscore:

Variant	Effect	Δscore
1:227924402:T:A	acceptor_loss	1.0000
1:227925259:TCAC:T	donor_loss	1.0000
1:227925260:CACC:C	donor_loss	1.0000
1:227925261:A:AC	donor_gain	1.0000
1:227925261:AC:A	donor_gain	1.0000
1:227925261:ACC:A	donor_loss	1.0000
1:227925261:ACCT:A	donor_gain	1.0000
1:227925262:C:CT	donor_gain	1.0000
1:227925262:CC:C	donor_gain	1.0000
1:227925262:CCT:C	donor_gain	1.0000
1:227925262:CCTC:C	donor_gain	1.0000
1:227925262:CCTCG:C	donor_gain	1.0000
1:227925520:C:CC	acceptor_gain	1.0000
1:227947788:CCTA:C	donor_loss	1.0000
1:227947789:CTA:C	donor_loss	1.0000
1:227947791:A:AC	donor_gain	1.0000
1:227947791:AC:A	donor_gain	1.0000
1:227947792:C:CC	donor_gain	1.0000
1:227947792:C:CT	donor_loss	1.0000
1:227947792:CC:C	donor_gain	1.0000
1:227922000:CCTG:C	acceptor_loss	0.9900
1:227922001:C:CA	acceptor_loss	0.9900
1:227922005:C:CT	acceptor_gain	0.9900
1:227922012:G:C	acceptor_gain	0.9900
1:227922012:G:GC	acceptor_gain	0.9900
1:227924148:A:AC	donor_gain	0.9900
1:227924149:C:CC	donor_gain	0.9900
1:227924364:G:T	acceptor_gain	0.9900
1:227924396:GAAGC:G	acceptor_gain	0.9900
1:227924397:AAGC:A	acceptor_gain	0.9900

AlphaMissense

2346 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:227921581:C:A	W345C	1.000
1:227921581:C:G	W345C	1.000
1:227921594:C:G	C341S	1.000
1:227921595:A:T	C341S	1.000
1:227921678:C:G	C313S	1.000
1:227921679:A:T	C313S	1.000
1:227921888:A:G	L243P	1.000
1:227921926:C:A	W230C	1.000
1:227921926:C:G	W230C	1.000
1:227921930:C:G	C229S	1.000
1:227921930:C:T	C229Y	1.000
1:227921931:A:T	C229S	1.000
1:227921945:C:G	C224S	1.000
1:227921945:C:T	C224Y	1.000
1:227921946:A:G	C224R	1.000
1:227921946:A:T	C224S	1.000
1:227921961:C:A	G219C	1.000
1:227921964:G:C	H218D	1.000
1:227921966:C:G	C217S	1.000
1:227921967:A:G	C217R	1.000
1:227921967:A:T	C217S	1.000
1:227921968:C:A	K216N	1.000
1:227921968:C:G	K216N	1.000
1:227921972:C:G	C215S	1.000
1:227921972:C:T	C215Y	1.000
1:227921973:A:T	C215S	1.000
1:227924208:A:C	F182C	1.000
1:227924250:C:G	C168S	1.000
1:227924251:A:T	C168S	1.000
1:227924258:C:A	W165C	1.000

dbSNP variants (sampled 300 via entrez): RS1000032877 (1:227948754 G>A), RS1000083639 (1:227944302 C>A,T), RS1000165428 (1:227923388 G>A), RS1000282343 (1:227928667 G>A), RS1000339230 (1:227923782 T>G), RS1000549602 (1:227949068 G>A), RS1000711285 (1:227940401 G>T), RS1000720436 (1:227935334 G>A,T), RS1000776073 (1:227919222 G>A,C), RS1000971501 (1:227920751 G>A), RS1000979610 (1:227939263 C>G,T), RS1000995547 (1:227940209 GC>G), RS1001034276 (1:227933236 A>G), RS1001077782 (1:227945144 G>A), RS1001259848 (1:227920553 C>T)

Disease associations

OMIM: gene MIM:602863 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003059_2	Parkinson’s disease	1.000000e-06
GCST003542_210	Night sleep phenotypes	7.000000e-06
GCST006137_5	Serum folate levels	7.000000e-06
GCST007094_215	Diastolic blood pressure	1.000000e-10
GCST007099_110	Systolic blood pressure	1.000000e-07
GCST008839_18	Height	3.000000e-18
GCST010173_174	Triglyceride levels	4.000000e-08
GCST010242_263	HDL cholesterol levels	2.000000e-09
GCST90000025_859	Appendicular lean mass	3.000000e-14
GCST90092003_2	Alcohol-related hepatocellular carcinoma	1.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation	2
aristolochic acid I	increases expression	1
bisphenol A	decreases expression	1
dimethylselenide	increases expression, increases oxidation, decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
avobenzone	decreases expression	1
deguelin	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Microplastics	increases abundance, decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Cannabinoids	affects methylation, increases abundance	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Fluorides	increases expression	1
Methapyrilene	increases methylation	1
Polystyrenes	decreases expression, increases abundance	1
Smoke	increases expression	1
Sodium Fluoride	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Triclosan	increases 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_E0T3	Ubigene HeLa WNT9A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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