WFIKKN2

Summary

WFIKKN2 (WAP, follistatin/kazal, immunoglobulin, kunitz and netrin domain containing 2, HGNC:30916) is a protein-coding gene on chromosome 17q21.33, encoding WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 (Q8TEU8). Protease-inhibitor that contains multiple distinct protease inhibitor domains.

The WFIKKN1 protein contains a WAP domain, follistatin domain, immunoglobulin domain, two tandem Kunitz domains, and an NTR domain. This gene encodes a WFIKKN1-related protein which has the same domain organization as the WFIKKN1 protein. The WAP-type, follistatin type, Kunitz-type, and NTR-type protease inhibitory domains may control the action of multiple types of proteases.

Source: NCBI Gene 124857 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 117 total
• MANE Select transcript: NM_175575

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30916
Approved symbol	WFIKKN2
Name	WAP, follistatin/kazal, immunoglobulin, kunitz and netrin domain containing 2
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	WFIKKNRP, WFDC20B
Ensembl gene	ENSG00000173714
Ensembl biotype	protein_coding
OMIM	610895
Entrez	124857

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000311378, ENST00000426127, ENST00000870048

RefSeq mRNA: 2 — MANE Select: NM_175575 NM_001330341, NM_175575

CCDS: CCDS11575, CCDS82159

Canonical transcript exons

ENST00000311378 — 2 exons

Exon	Start	End
ENSE00001189389	50839499	50842353
ENSE00001189401	50835586	50836147

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 94.56.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7569 / max 399.5489, expressed in 84 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161727	0.3260	39
161726	0.3081	51
161725	0.0475	15
161728	0.0275	7
161723	0.0150	8
161729	0.0122	7
161722	0.0117	3
161724	0.0051	3
208264	0.0040	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	94.56	gold quality
right ovary	UBERON:0002118	90.29	gold quality
ovary	UBERON:0000992	87.95	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.65	silver quality
pigmented layer of retina	UBERON:0001782	74.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	68.41	gold quality
ventricular zone	UBERON:0003053	67.61	gold quality
right adrenal gland cortex	UBERON:0035827	65.12	gold quality
adrenal tissue	UBERON:0018303	64.20	gold quality
cerebellar vermis	UBERON:0004720	63.57	gold quality
right adrenal gland	UBERON:0001233	63.17	gold quality
left adrenal gland	UBERON:0001234	62.88	gold quality
cerebellar hemisphere	UBERON:0002245	61.93	gold quality
cerebellar cortex	UBERON:0002129	61.88	gold quality
endothelial cell	CL:0000115	61.82	gold quality
left adrenal gland cortex	UBERON:0035825	61.82	gold quality
cerebellum	UBERON:0002037	61.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.19	gold quality
adrenal cortex	UBERON:0001235	60.95	gold quality
adrenal gland	UBERON:0002369	60.53	gold quality
tibia	UBERON:0000979	60.50	silver quality
muscle of leg	UBERON:0001383	60.09	gold quality
myocardium	UBERON:0002349	59.94	gold quality
vena cava	UBERON:0004087	58.78	gold quality
gastrocnemius	UBERON:0001388	58.65	gold quality
right atrium auricular region	UBERON:0006631	57.70	gold quality
tibial nerve	UBERON:0001323	57.56	gold quality
amniotic fluid	UBERON:0000173	57.40	gold quality
cardiac atrium	UBERON:0002081	57.25	gold quality
pituitary gland	UBERON:0000007	57.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

75 targeting WFIKKN2, 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-4283	100.00	66.42	2097
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-4292	99.16	65.57	1767

Literature-anchored findings (GeneRIF, showing 8)

• Newly discovered WFIKKNPR gene structure and tissue distribution of gene expression is commpared with that of the WFIKKN gene in adult and fetal tissues and organs (PMID:11928817)
• Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11. (PMID:18596030)
• Creatine supplementation in conjunction with resistance training lead to greater decreases in serum myostatin (p<0.05), but had not additional effect on GASP-1 (p>0.05). (PMID:20026378)
• data indicate that WFIKKN proteins are antagonists of GDF8 and GDF11, but in the case of TGFbeta1, BMP2 and BMP4 they function as growth factor binding proteins (PMID:21054789)
• After eccentric exercise, postmenopausal women not using hormone therapy (HT) expressed higher levels of GASP-1 while postmenopausal women using HT showed a significant increased expression over controls. (PMID:22395277)
• Data suggest that myostatin binding to its receptor (activin receptors type II) can be blocked by WFIKKN1 but not WFIKKN2; various forms of myostatin (promyostatin, myostatin pro-domain, and latent/processed myostatin) bind WFIKKN1 but not WFIKKN2. (PMID:23829672)
• In this review, we summarize current knowledge about the WFIKKN proteins and propose that they are “companion” proteins for various growth factors by providing localized and sustained presentation of TGFB proteins to their respective receptors, thus regulating the balance between the activation of Smad and non-Smad pathways by TGFB. (PMID:27325460)
• WFIKKN2 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Wfikkn2	ENSMUSG00000044177
rattus_norvegicus	Wfikkn2	ENSRNOG00000002831
drosophila_melanogaster	CG7565	FBGN0035833
caenorhabditis_elegans		WBGENE00010792
caenorhabditis_elegans		WBGENE00015355
caenorhabditis_elegans		WBGENE00021939

Paralogs (13): TFPI (ENSG00000003436), EPPIN (ENSG00000101448), TFPI2 (ENSG00000105825), AMBP (ENSG00000106927), LRP11 (ENSG00000120256), WFIKKN1 (ENSG00000127578), KIAA0319 (ENSG00000137261), KIAA0319L (ENSG00000142687), SPINT4 (ENSG00000149651), WFDC8 (ENSG00000158901), SPINT1 (ENSG00000166145), SPINT2 (ENSG00000167642), WFDC6 (ENSG00000243543)

Protein

Protein identifiers

WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 — Q8TEU8 (reviewed: Q8TEU8)

Alternative names: Growth and differentiation factor-associated serum protein 1, WAP, follistatin, immunoglobulin, Kunitz and NTR domain-containing-related protein, WFIKKN-related protein

All UniProt accessions (2): Q8TEU8, C9J6G4

UniProt curated annotations — full annotation on UniProt →

Function. Protease-inhibitor that contains multiple distinct protease inhibitor domains. Probably has serine protease- and metalloprotease-inhibitor activity. Inhibits the biological activity of mature myostatin, but not activin.

Subunit / interactions. Interacts with both mature and propeptide myostatin/MSTN.

Subcellular location. Secreted.

Tissue specificity. Primarily expressed in ovary, testis and brain, but not in liver. In fetal tissues, it is primarily expressed in brain, skeletal muscle, thymus and kidney.

Similarity. Belongs to the WFIKKN family.

RefSeq proteins (2): NP_001317270, NP_783165* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001134	Netrin_domain	Domain
IPR002223	Kunitz_BPTI	Domain
IPR002350	Kazal_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR008197	WAP_dom	Domain
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR018933	Netrin_module_non-TIMP	Domain
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR033638	WFIKKN1/2_Ig-like_3	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036645	Elafin-like_sf	Homologous_superfamily
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily

Pfam: PF00014, PF00095, PF01759, PF07679

UniProt features (30 total): disulfide bond 17, domain 6, glycosylation site 2, sequence variant 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEU8-F1	76.00	0.22

Functional residue map

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

Catalytic / active sites (1): 140–141 (reactive bond)

Disulfide bonds (17): 46–79, 62–83, 66–78, 72–88, 134–164, 138–157, 146–175, 231–287, 328–378, 337–361, 353–374, 386–436, 395–419, 411–432, 445–515, 448–517, 459–566

Glycosylation sites (2): 519, 319

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): AHRARNT_01, RNGTGGGC_UNKNOWN, FXR_IR1_Q6, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, MYOGENIN_Q6, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, FOXO4_01, FOXO1_01, TCF4_Q5, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, MYOD_01, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, WTGAAAT_UNKNOWN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN

GO Biological Process (5): skeletal system development (GO:0001501), transforming growth factor beta receptor signaling pathway (GO:0007179), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), muscle cell development (GO:0055001), roof of mouth development (GO:0060021)

GO Molecular Function (6): serine-type endopeptidase inhibitor activity (GO:0004867), receptor antagonist activity (GO:0048019), transforming growth factor beta binding (GO:0050431), enzyme inhibitor activity (GO:0004857), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
muscle cell differentiation	1
cell development	1
anatomical structure development	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
signaling receptor binding	1
signaling receptor inhibitor activity	1
growth factor binding	1
cytokine binding	1
catalytic activity	1
enzyme regulator activity	1
molecular function inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

608 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WFIKKN2	MSTN	O14793	919
WFIKKN2	GDF11	O95390	870
WFIKKN2	NTSR1	P30989	850
WFIKKN2	FST	P19883	845
WFIKKN2	FSTL3	O95633	624
WFIKKN2	BMP4	P12644	485
WFIKKN2	BMP2	P12643	479
WFIKKN2	FIBCD1	Q8N539	456
WFIKKN2	PAEP	P09466	439
WFIKKN2	TGFB1	P01137	396
WFIKKN2	ACVR1C	Q8NER5	384
WFIKKN2	PRAMEF20	Q5VT98	381
WFIKKN2	TMEM9	Q9P0T7	367
WFIKKN2	HDGFL2	Q7Z4V5	366
WFIKKN2	SAAL1	Q96ER3	341

IntAct

17 interactions, top by confidence:

A	B	Type	Score
IGDCC3	WFIKKN2	psi-mi:“MI:0915”(physical association)	0.540
WFIKKN2	IGDCC4	psi-mi:“MI:0915”(physical association)	0.540
PRTG	WFIKKN2	psi-mi:“MI:0915”(physical association)	0.540
IGDCC3	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.540
IGDCC4	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.540
PRTG	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.540
DCC	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.440
WFIKKN2	IL6R	psi-mi:“MI:0407”(direct interaction)	0.440
BMP4	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.440
TGFB1	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.440
WFIKKN2	BMP2	psi-mi:“MI:0407”(direct interaction)	0.440
BMP3	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.440
BMP8B	WFIKKN2	psi-mi:“MI:0407”(direct interaction)	0.440
WFIKKN2	Mstn	psi-mi:“MI:0915”(physical association)	0.400
GDF11	WFIKKN2	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A096LNW5, B8JI71, D3ZHH1, G3I6Z6, O00548, O35516, O57409, P0DPK3, P0DPK4, P35442, P46531, P78504, P97677, Q01705, Q04721, Q05793, Q07008, Q08E66, Q2QI47, Q5G872, Q5ZQU0, Q61483, Q63722, Q66PY1, Q6DI48, Q6NZL8, Q70E20, Q7TQN3, Q7Z3S9, Q8IWY4, Q8IX30, Q8JZM4, Q8K3K1, Q8NFT8, Q8TER0, Q8TEU8, Q8UWJ4, Q8VHS2, Q90Y54, Q90Y57

Diamond homologs: A0A1D0BND9, A0A3G2FQK2, A0A6B7FA07, A0A6B7FBD3, A0A6B7FEJ3, A0A6P8HC43, A5X2X1, A6MFL3, A8Y7N5, A8Y7P3, A8Y7P4, B1B5I8, B2G331, B6ZIW0, C0HJF3, C0HJF4, C0HJU6, C0HJU7, C0HK72, C0HK73, C0HK74, C0HMC7, C1IBY4, C1IC51, C1IC52, C8YJ94, C8YJ95, C8YJ96, C8YJ97, D4A2Z2, F6ULY1, H2A0N5, H2A0P0, H6VC06, O35536, O54819, O62845, O76840, P00978, P00993

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

212 predictions. Top by Δscore:

Variant	Effect	Δscore
17:50836144:CCAG:C	donor_loss	0.9900
17:50836145:CAG:C	donor_loss	0.9900
17:50836146:AG:A	donor_loss	0.9900
17:50836147:GG:G	donor_loss	0.9900
17:50836148:G:GA	donor_loss	0.9900
17:50836149:T:G	donor_loss	0.9900
17:50839497:A:AG	acceptor_gain	0.9900
17:50839498:G:GG	acceptor_gain	0.9900
17:50839498:GGA:G	acceptor_gain	0.9900
17:50839498:GGAGT:G	acceptor_gain	0.9900
17:50836150:GA:G	donor_loss	0.9800
17:50839495:TCAG:T	acceptor_loss	0.9800
17:50839496:CAGGA:C	acceptor_loss	0.9800
17:50839497:A:AT	acceptor_loss	0.9800
17:50839497:AG:A	acceptor_gain	0.9800
17:50839498:G:T	acceptor_loss	0.9800
17:50839498:GG:G	acceptor_gain	0.9800
17:50835824:A:T	donor_gain	0.9700
17:50835823:G:GT	donor_gain	0.9500
17:50839496:CAGG:C	acceptor_gain	0.9500
17:50839497:AGGA:A	acceptor_gain	0.9500
17:50839498:GGAG:G	acceptor_gain	0.9500
17:50836148:G:GG	donor_gain	0.9200
17:50840999:G:GT	donor_gain	0.9200
17:50836129:G:GT	donor_gain	0.9000
17:50840998:G:GT	donor_gain	0.8900
17:50837349:G:GT	donor_gain	0.8400
17:50836148:G:C	donor_gain	0.8200
17:50836149:T:A	donor_gain	0.8200
17:50836145:CAGG:C	donor_gain	0.8100

AlphaMissense

3804 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:50840017:G:C	W243C	1.000
17:50840017:G:T	W243C	1.000
17:50836102:G:C	W55C	0.999
17:50836102:G:T	W55C	0.999
17:50840015:T:A	W243R	0.999
17:50840015:T:C	W243R	0.999
17:50840149:C:G	C287W	0.999
17:50840320:G:C	W344C	0.999
17:50840320:G:T	W344C	0.999
17:50836073:T:A	C46S	0.998
17:50836073:T:C	C46R	0.998
17:50836074:G:A	C46Y	0.998
17:50836074:G:C	C46S	0.998
17:50839502:T:A	C72S	0.998
17:50839503:G:C	C72S	0.998
17:50839535:T:A	C83S	0.998
17:50839536:G:C	C83S	0.998
17:50839550:T:A	C88S	0.998
17:50839550:T:C	C88R	0.998
17:50839551:G:A	C88Y	0.998
17:50839551:G:C	C88S	0.998
17:50839688:T:A	C134S	0.998
17:50839689:G:C	C134S	0.998
17:50839724:T:A	C146S	0.998
17:50839725:G:C	C146S	0.998
17:50839979:T:A	C231S	0.998
17:50839979:T:C	C231R	0.998
17:50839980:G:A	C231Y	0.998
17:50839980:G:C	C231S	0.998
17:50840103:T:C	L272P	0.998

dbSNP variants (sampled 300 via entrez): RS1000136424 (17:50839165 T>C), RS1001032025 (17:50838295 AG>A), RS1001137102 (17:50838485 G>A), RS1001237667 (17:50839207 G>A,C), RS1001701765 (17:50833044 G>T), RS1001753987 (17:50833207 C>T), RS1001998182 (17:50838664 G>A), RS1002433845 (17:50842390 G>A), RS1002864977 (17:50837827 T>C), RS1002897021 (17:50838186 A>T), RS1003060053 (17:50837507 C>A), RS1003074914 (17:50832840 C>G,T), RS1003234084 (17:50837023 G>A), RS1003373233 (17:50841806 G>A,C), RS1003421089 (17:50832685 C>A,T)

Disease associations

OMIM: gene MIM:610895 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006479_46	Diverticular disease	4.000000e-06
GCST009440_12	Age-related cognitive decline (attention/processing speed) (slope of z-scores)	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease
EFO:0007710	cognitive decline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Aflatoxin B1	increases expression, increases methylation	2
bisphenol A	affects cotreatment, increases methylation	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects methylation, increases abundance	1
Endosulfan	increases expression	1
Methotrexate	increases expression	1
Valproic Acid	increases methylation	1
Particulate Matter	affects methylation, increases abundance	1
Magnetite Nanoparticles	increases expression	1

Clinical trials (associated diseases)

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