WFIKKN1

Summary

WFIKKN1 (WAP, follistatin/kazal, immunoglobulin, kunitz and netrin domain containing 1, HGNC:30912) is a protein-coding gene on chromosome 16p13.3, encoding WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (Q96NZ8). Protease-inhibitor that contains multiple distinct protease inhibitor domains.

This gene encodes a secreted multidomain protein consisting of a signal peptide, a WAP domain, a follistatin domain, an immunoglobulin domain, two tandem Kunitz domains, and an NTR domain. These domains have been implicated frequently in inhibition of various types of proteases, suggesting that the encoded protein may be a multivalent protease inhibitor and may control the action of multiple types of serine proteases as well as metalloproteinases.

Source: NCBI Gene 117166 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 152 total
• MANE Select transcript: NM_053284

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30912
Approved symbol	WFIKKN1
Name	WAP, follistatin/kazal, immunoglobulin, kunitz and netrin domain containing 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	RJD2, WFIKKN, WFDC20A
Ensembl gene	ENSG00000127578
Ensembl biotype	protein_coding
OMIM	608021
Entrez	117166

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000319070, ENST00000573440

RefSeq mRNA: 1 — MANE Select: NM_053284 NM_053284

CCDS: CCDS10414

Canonical transcript exons

ENST00000319070 — 2 exons

Exon	Start	End
ENSE00001061905	630985	631424
ENSE00001239712	632582	634117

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 77.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7410 / max 28.0719, expressed in 149 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151954	0.7410	149

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	77.25	gold quality
cerebellar hemisphere	UBERON:0002245	76.84	gold quality
cerebellar cortex	UBERON:0002129	76.68	gold quality
cerebellum	UBERON:0002037	75.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.83	gold quality
mucosa of transverse colon	UBERON:0004991	68.02	gold quality
right frontal lobe	UBERON:0002810	65.57	gold quality
pituitary gland	UBERON:0000007	65.46	gold quality
putamen	UBERON:0001874	65.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	63.78	gold quality
anterior cingulate cortex	UBERON:0009835	63.48	gold quality
adenohypophysis	UBERON:0002196	63.25	gold quality
nucleus accumbens	UBERON:0001882	63.14	gold quality
skin of abdomen	UBERON:0001416	63.13	gold quality
caudate nucleus	UBERON:0001873	63.08	gold quality
ventricular zone	UBERON:0003053	62.98	gold quality
lower esophagus mucosa	UBERON:0035834	62.94	gold quality
right uterine tube	UBERON:0001302	62.59	gold quality
gingival epithelium	UBERON:0001949	62.54	gold quality
right lobe of thyroid gland	UBERON:0001119	62.48	gold quality
amygdala	UBERON:0001876	62.46	gold quality
skin of leg	UBERON:0001511	62.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	62.27	gold quality
brain	UBERON:0000955	62.05	gold quality
right lobe of liver	UBERON:0001114	62.04	gold quality
ganglionic eminence	UBERON:0004023	62.03	gold quality
adult mammalian kidney	UBERON:0000082	61.94	gold quality
cortical plate	UBERON:0005343	61.93	gold quality
gastrocnemius	UBERON:0001388	61.86	gold quality
primary visual cortex	UBERON:0002436	61.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.42

Regulation

Is transcription factor: no

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)
• Data suggest that the physiological target of WFIKKN protein may be trypsin. (PMID:12709070)
• three-dimensional structure of a Kunitz domain with a tryptophan residue at the P02 site of the protease-recognition loop (PMID:16791741)
• Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11. (PMID:18596030)
• 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)
• 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)
• Data show that the KKN1 fragment generated by BMP1-cleavage of WFIKKN1 protein contributes most significantly to the observed enhancer activity. (PMID:27782377)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	wfikkn2a	ENSDARG00000013460
danio_rerio	wfikkn2b	ENSDARG00000059139
mus_musculus	Wfikkn1	ENSMUSG00000071192
rattus_norvegicus	Wfikkn1	ENSRNOG00000021578
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), KIAA0319 (ENSG00000137261), KIAA0319L (ENSG00000142687), SPINT4 (ENSG00000149651), WFDC8 (ENSG00000158901), SPINT1 (ENSG00000166145), SPINT2 (ENSG00000167642), WFIKKN2 (ENSG00000173714), WFDC6 (ENSG00000243543)

Protein

Protein identifiers

WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 — Q96NZ8 (reviewed: Q96NZ8)

Alternative names: Growth and differentiation factor-associated serum protein 2, WAP, follistatin, immunoglobulin, Kunitz and NTR domain-containing protein

All UniProt accessions (1): Q96NZ8

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.

Subcellular location. Secreted.

Tissue specificity. Expressed in pancreas, kidney, liver, placenta, and lung.

Domain organisation. The second BPTI/Kunitz inhibitor domain is able to inhibit trypsin. It has however no activity toward chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator.

Similarity. Belongs to the WFIKKN family.

RefSeq proteins (1): NP_444514* (*=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
IPR013783	Ig-like_fold	Homologous_superfamily
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, PF13927

UniProt features (36 total): disulfide bond 17, domain 6, strand 5, helix 3, signal peptide 1, chain 1, glycosylation site 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2DDI	SOLUTION NMR
2DDJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NZ8-F1	78.59	0.27

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): 122–123 (reactive bond)

Disulfide bonds (17): 33–66, 49–70, 53–65, 59–75, 116–146, 120–139, 128–157, 207–263, 299–351, 306–334, 326–347, 359–409, 368–392, 384–405, 417–489, 420–491, 431–540

Glycosylation sites (1): 493

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 62 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, LIAO_METASTASIS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, GOBP_RESPONSE_TO_GROWTH_FACTOR, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_TRANSFORMING_GROWTH_FACTOR_BETA_RECEPTOR_SIGNALING_PATHWAY, GOBP_MUSCLE_CELL_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_MUSCLE_CELL_DIFFERENTIATION, NIKOLSKY_BREAST_CANCER_16P13_AMPLICON, GOMF_PEPTIDASE_REGULATOR_ACTIVITY

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

482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WFIKKN1	NTSR1	P30989	875
WFIKKN1	FST	P19883	871
WFIKKN1	GDF11	O95390	715
WFIKKN1	MSTN	O14793	667
WFIKKN1	CTRB2	Q6GPI1	609
WFIKKN1	CTRB1	P17538	574
WFIKKN1	SLPI	P03973	552
WFIKKN1	FSTL3	O95633	525
WFIKKN1	BMP4	P12644	522
WFIKKN1	SULT6B1	Q6IMI4	509
WFIKKN1	PAEP	P09466	477
WFIKKN1	BMP2	P12643	459
WFIKKN1	BMP15	O95972	437
WFIKKN1	BMP10	O95393	433
WFIKKN1	GDF9	O60383	430

IntAct

18 interactions, top by confidence:

A	B	Type	Score
APPBP2	WFIKKN1	psi-mi:“MI:0915”(physical association)	0.560
WFIKKN1	MSTN	psi-mi:“MI:0407”(direct interaction)	0.560
MSTN	WFIKKN1	psi-mi:“MI:0407”(direct interaction)	0.560
WFIKKN1	BMP4	psi-mi:“MI:0407”(direct interaction)	0.440
TGFB1	WFIKKN1	psi-mi:“MI:0407”(direct interaction)	0.440
WFIKKN1	BMP2	psi-mi:“MI:0407”(direct interaction)	0.440
BMP3	WFIKKN1	psi-mi:“MI:0407”(direct interaction)	0.440
BMP8B	WFIKKN1	psi-mi:“MI:0407”(direct interaction)	0.440
WFIKKN1	H1-5	psi-mi:“MI:0915”(physical association)	0.400
WFIKKN1	Mstn	psi-mi:“MI:0915”(physical association)	0.400
WFIKKN1	GDF11	psi-mi:“MI:0915”(physical association)	0.400
WFIKKN1	CSNK2B	psi-mi:“MI:0915”(physical association)	0.370
WFIKKN1	DCAF10	psi-mi:“MI:0914”(association)	0.350
WFIKKN1	APPBP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): WFIKKN1 (Two-hybrid), WFIKKN1 (Proximity Label-MS), WFIKKN1 (Affinity Capture-RNA), SLC25A30 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), TRAF7 (Affinity Capture-MS), DCAF10 (Affinity Capture-MS), WFIKKN1 (Two-hybrid)

ESM2 similar proteins: A1A5Y0, A2ASQ1, O00468, O00548, O57409, O89103, O95428, P06579, P07204, P0C5J5, P15306, P20063, P25304, P31696, P97607, P97677, P98160, Q05793, Q08E66, Q14112, Q2PC93, Q501P1, Q53RD9, Q5W7P8, Q61483, Q61810, Q66PY1, Q6NUX0, Q6NZL8, Q6ZRI0, Q71U07, Q75N90, Q7T3Q2, Q8IWY4, Q8IX30, Q8JZM4, Q8NFT8, Q8R0S6, Q8R4Y4, Q8VIK5

Diamond homologs: A0A1D0BND9, A0A3G2FQK2, A0A6B7FA07, A0A6B7FBD3, A0A6B7FEJ3, A0A6P8HC43, A5X2X1, A8Y7N9, A8Y7P0, A8Y7P6, B1B5I8, B2BS84, B5KF95, B5KL37, B5KL38, B5L5R7, B6RLX2, B6ZIW0, C0HJF3, C0HK74, C0HLB2, C0HMC7, C1IC52, C8YJ94, D8KY58, G3LH89, H2A0N1, H2A0P0, O35536, O43278, O43291, O54819, O76840, P00978, P00990, P00991, P02760, P04365, P04366, P0DJ50

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 12 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of SMAD protein signal transduction	5	174.1×	2e-08
negative regulation of cell population proliferation	5	19.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	144
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

222 predictions. Top by Δscore:

Variant	Effect	Δscore
16:632576:CCCCA:C	acceptor_loss	0.9900
16:632578:CCAG:C	acceptor_loss	0.9900
16:632579:CA:C	acceptor_loss	0.9900
16:632581:GGACT:G	acceptor_gain	0.9900
16:632580:A:AG	acceptor_gain	0.9800
16:632581:G:GG	acceptor_gain	0.9800
16:632580:AG:A	acceptor_gain	0.9700
16:632581:GG:G	acceptor_gain	0.9700
16:632581:GGAC:G	acceptor_gain	0.9700
16:631123:G:GT	donor_gain	0.9500
16:632581:GGA:G	acceptor_gain	0.9300
16:631425:G:GG	donor_gain	0.9200
16:632444:GACAC:G	donor_gain	0.8800
16:632574:A:AG	acceptor_gain	0.8400
16:632215:ATCCG:A	acceptor_gain	0.7800
16:632219:G:A	acceptor_gain	0.7600
16:631182:G:GT	donor_gain	0.7300
16:632404:G:GA	donor_gain	0.7300
16:632215:ATCC:A	acceptor_gain	0.7100
16:632390:AAG:A	donor_loss	0.7100
16:632391:AG:A	donor_loss	0.7100
16:632392:GGTAA:G	donor_loss	0.7100
16:632393:G:C	donor_loss	0.7100
16:632394:TAA:T	donor_loss	0.7100
16:632575:T:G	acceptor_gain	0.7100
16:631101:GCT:G	donor_gain	0.7000
16:632395:AA:A	donor_loss	0.7000
16:632585:T:A	acceptor_gain	0.6900
16:632218:C:CA	acceptor_gain	0.6800
16:632403:T:TA	donor_gain	0.6800

AlphaMissense

3560 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:633067:G:C	W219C	1.000
16:633067:G:T	W219C	1.000
16:633065:T:A	W219R	0.999
16:633065:T:C	W219R	0.999
16:633361:G:C	W317C	0.999
16:633361:G:T	W317C	0.999
16:631379:G:C	W42C	0.998
16:631379:G:T	W42C	0.998
16:633191:T:G	Y261D	0.998
16:633197:T:C	C263R	0.998
16:633198:G:A	C263Y	0.998
16:633199:C:G	C263W	0.998
16:633066:G:C	W219S	0.997
16:633153:T:C	L248P	0.997
16:633197:T:A	C263S	0.997
16:633198:G:C	C263S	0.997
16:633714:T:G	F435C	0.997
16:633029:T:A	C207S	0.996
16:633030:G:A	C207Y	0.996
16:633030:G:C	C207S	0.996
16:633714:T:C	F435S	0.996
16:632787:T:G	F126C	0.995
16:632792:T:A	C128S	0.995
16:632793:G:C	C128S	0.995
16:633029:T:C	C207R	0.995
16:632608:C:G	C66W	0.994
16:632633:T:A	C75S	0.994
16:632634:G:C	C75S	0.994
16:632825:T:A	C139S	0.994
16:632826:G:C	C139S	0.994

dbSNP variants (sampled 300 via entrez): RS1001071552 (16:629681 G>A,C,T), RS1001194663 (16:630039 C>A,T), RS1002233269 (16:629136 C>T), RS1003546595 (16:630915 C>T), RS1003578086 (16:633641 G>A,C), RS1003631912 (16:633763 C>T), RS1004607668 (16:630965 TGGGAGCCCCCGCAC>T), RS1004959205 (16:631480 C>G,T), RS1005423981 (16:634423 C>G,T), RS1005589930 (16:630776 C>A,T), RS1007104911 (16:630607 C>T), RS1007382594 (16:634193 G>A), RS1008104250 (16:629796 C>G,T), RS1008133999 (16:631151 G>A,T), RS1008899748 (16:632766 G>A)

Disease associations

OMIM: gene MIM:608021 | 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
GCST006585_1079	Blood protein levels	2.000000e-13
GCST008163_93	Height	6.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression, affects expression	7
Arsenic	decreases expression, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	increases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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