SPINK9

Summary

SPINK9 (serine peptidase inhibitor Kazal type 9, HGNC:32951) is a protein-coding gene on chromosome 5q32, encoding Serine protease inhibitor Kazal-type 9 (Q5DT21). Serine protease inhibitor which specifically inhibits KLK5.

The protein encoded by this gene is a Kazal-type serine protease inhibitor that appears to specifically target kallikrein-related peptidase 5 (KLK5) in the palmo-plantar epidermis. KLK5 is an important initiator of skin desquamation, so the encoded protease inhibitor may regulate skin differentiation in the palms of hands and soles of feet. This cationic protein has also been shown to promote keratinocyte migration by activation of the epidermal growth factor receptor (EGFR).

Source: NCBI Gene 643394 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• MANE Select transcript: NM_001040433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32951
Approved symbol	SPINK9
Name	serine peptidase inhibitor Kazal type 9
Location	5q32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204909
Ensembl biotype	protein_coding
OMIM	613511
Entrez	643394

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000377906, ENST00000511717

RefSeq mRNA: 1 — MANE Select: NM_001040433 NM_001040433

CCDS: CCDS34269

Canonical transcript exons

ENST00000377906 — 4 exons

Exon	Start	End
ENSE00001475460	148339667	148339852
ENSE00001475461	148338478	148338605
ENSE00001475462	148336422	148336453
ENSE00001475463	148335559	148335668

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 87.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0274 / max 39.5382, expressed in 5 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59312	0.0274	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.70	gold quality
corpus callosum	UBERON:0002336	79.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.68	silver quality
adrenal tissue	UBERON:0018303	63.89	gold quality
calcaneal tendon	UBERON:0003701	58.55	gold quality
cortical plate	UBERON:0005343	53.04	gold quality
nucleus accumbens	UBERON:0001882	51.30	gold quality
anterior cingulate cortex	UBERON:0009835	50.14	gold quality
Brodmann (1909) area 9	UBERON:0013540	49.66	gold quality
right atrium auricular region	UBERON:0006631	49.48	gold quality
granulocyte	CL:0000094	49.13	silver quality
fundus of stomach	UBERON:0001160	49.12	gold quality
right adrenal gland	UBERON:0001233	48.55	gold quality
right adrenal gland cortex	UBERON:0035827	48.41	gold quality
hypothalamus	UBERON:0001898	48.19	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	47.99	gold quality
putamen	UBERON:0001874	47.45	gold quality
body of pancreas	UBERON:0001150	47.38	gold quality
cerebral cortex	UBERON:0000956	47.27	gold quality
right frontal lobe	UBERON:0002810	47.27	gold quality
caudate nucleus	UBERON:0001873	46.89	gold quality
frontal cortex	UBERON:0001870	46.84	gold quality
left adrenal gland	UBERON:0001234	46.45	gold quality
adrenal gland	UBERON:0002369	46.22	gold quality
brain	UBERON:0000955	46.11	gold quality
right hemisphere of cerebellum	UBERON:0014890	45.97	gold quality
heart	UBERON:0000948	45.96	gold quality
left adrenal gland cortex	UBERON:0035825	45.91	gold quality
prefrontal cortex	UBERON:0000451	45.87	gold quality
primary visual cortex	UBERON:0002436	45.63	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	37.33
E-ANND-3	yes	2.58
E-CURD-135	no	1718.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting SPINK9, 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-5580-3P	99.70	69.41	2052
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-4686	98.77	66.87	964
HSA-MIR-581	98.39	67.42	835
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-7850-5P	98.12	67.28	1111
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-6806-5P	96.37	68.74	587
HSA-MIR-5009-5P	94.82	63.89	775
HSA-MIR-8058	94.76	63.41	632
HSA-MIR-1269A	92.75	64.61	542
HSA-MIR-1269B	92.75	64.73	538

Literature-anchored findings (GeneRIF, showing 5)

• A new KLK5-inhibiting peptide encoded by a member of the Spink family, designated as Spink9 located on chromosome 5p33.1, was identified. (PMID:19190773)
• possible role for SPINK9 in the site-specific epidermal differentiation of palms and soles (PMID:19194479)
• mSPINK12 shows an inhibitory activity against murine keratinocyte-derived trypsin-like proteolytic activity, and thus, appears orthologous to human LEKTI2 and may play an role in the regulation of epithelial cell functions. (PMID:21899598)
• the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14 (PMID:22505519)
• SPINK9 has a role in stimulating metalloprotease/EGFR-dependent keratinocyte migration by purinergic receptor pathway activation (PMID:24441102)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spink10	ENSMUSG00000044176
mus_musculus	Spinkl	ENSMUSG00000053729
mus_musculus	Spink11	ENSMUSG00000073573
rattus_norvegicus	Spink10	ENSRNOG00000043250
rattus_norvegicus		ENSRNOG00000063574

Paralogs (5): SPINK2 (ENSG00000128040), SPINK7 (ENSG00000145879), SPINK14 (ENSG00000196800), SPINK13 (ENSG00000214510), SPINK8 (ENSG00000229453)

Protein

Protein identifiers

Serine protease inhibitor Kazal-type 9 — Q5DT21 (reviewed: Q5DT21)

Alternative names: Lymphoepithelial Kazal-type-related inhibitor 2

All UniProt accessions (2): D6RJC5, Q5DT21

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease inhibitor which specifically inhibits KLK5. May contribute to the regulation of the desquamation process in skin by inhibiting KLK5.

Subunit / interactions. Dimer. Interacts with KLK5 and KLK8.

Subcellular location. Secreted.

Tissue specificity. Skin. Highly expressed at sites of hyperkeratosis. Also detected in thymus, tonsils, testis, pancreas, liver, placenta and brain. Expressed at stratum granulosum and stratum corneum at palmar and plantar sites (at protein level).

RefSeq proteins (1): NP_001035523* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001239	Prot_inh_Kazal-m	Family
IPR002350	Kazal_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR050159	Kazal-type_SerProtInhib	Family

Pfam: PF00050

UniProt features (8 total): disulfide bond 3, signal peptide 1, chain 1, domain 1, site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5DT21-F1	91.16	0.76

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): 48–49 (reactive bond)

Disulfide bonds (3): 32–68, 46–65, 54–86

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 22 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEOLYSIS, chr5q32, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_REGULATOR_ACTIVITY, ZHENG_IL22_SIGNALING_UP, GOMF_SERINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, GOBP_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_B, GOMF_ENDOPEPTIDASE_REGULATOR_ACTIVITY, REACTOME_KERATINIZATION, REACTOME_FORMATION_OF_THE_CORNIFIED_ENVELOPE

GO Biological Process (0):

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
serine-type endopeptidase activity	1
endopeptidase 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

412 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPINK9	KLK8	O60259	923
SPINK9	ING1	Q9UK53	890
SPINK9	SPINK14	Q6IE38	729
SPINK9	SPINK5	Q9NQ38	627
SPINK9	OR1E1	P30953	589
SPINK9	FXYD4	P59646	571
SPINK9	KLK14	Q9P0G3	544
SPINK9	SPINK13	Q1W4C9	542
SPINK9	COXFA4L2	Q9NRX3	527
SPINK9	D6RI10	D6RI10	523
SPINK9	KLK7	P49862	523
SPINK9	PILRA	Q9UKJ1	506
SPINK9	KLK6	Q92876	481
SPINK9	UNC45B	Q8IWX7	475
SPINK9	SPATA18	Q8TC71	474

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SGTA	SPINK9	psi-mi:“MI:0915”(physical association)	0.560
SPINK9	SGTA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): SPINK9 (Positive Genetic), SPINK9 (Two-hybrid)

ESM2 similar proteins: A0A1R3S3A8, A0A218QX39, A0A2R4SV19, A0A6B9KZ59, A0A6B9KZ79, A0A6B9KZ83, A0A6B9KZ89, A0A6B9L3M7, A0A7M7H308, B0JFB8, B2ZBB6, B3EWF2, B5M0W4, F5GTK6, H1ZZI0, H2A0M2, H2A0N9, L0GCJ1, L0GCW8, O46162, O46163, O77417, O77418, P09655, P09656, P0C8W3, P0CI85, P0DJ76, P0DM30, P0DMZ3, P0DMZ4, P0DN00, P0DN02, P0DQG9, P0DRC0, P0DRC1, P0DRC2, P0DRJ0, P0DUS7, P0DY44

Diamond homologs: D3ZVP0, O35679, P01003, P83579, Q1W4C9, Q3UTS8, Q5DT21, A2ASQ1, A5YT95, O60575, O62650, O95633, P00995, P00996, P00997, P00998, P01005, P04542, P05560, P09036, P09655, P09656, P0C7L1, P0DKM8, P0DKM9, P0DKT1, P0DKT2, P0DKT3, P0DKT4, P0DKT5, P10184, P10669, P11706, P16226, P19883, P20155, P21674, P25304, P31514, P31696

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

260 predictions. Top by Δscore:

Variant	Effect	Δscore
5:148335664:GTTCA:G	donor_gain	1.0000
5:148335669:G:GG	donor_gain	1.0000
5:148338474:TCAG:T	acceptor_loss	1.0000
5:148338475:CA:C	acceptor_loss	1.0000
5:148338476:A:AC	acceptor_loss	1.0000
5:148338476:A:AG	acceptor_gain	1.0000
5:148338476:AGGTT:A	acceptor_gain	1.0000
5:148338477:G:GG	acceptor_gain	1.0000
5:148338477:G:GT	acceptor_loss	1.0000
5:148338477:GGTT:G	acceptor_gain	1.0000
5:148338477:GGTTG:G	acceptor_gain	1.0000
5:148338601:GTTAA:G	donor_gain	1.0000
5:148338602:T:G	donor_gain	1.0000
5:148338602:TTAA:T	donor_gain	1.0000
5:148338603:TAA:T	donor_gain	1.0000
5:148338606:G:GG	donor_gain	1.0000
5:148335665:TTCA:T	donor_gain	0.9900
5:148336450:GATG:G	donor_gain	0.9900
5:148338476:AG:A	acceptor_gain	0.9900
5:148338477:GG:G	acceptor_gain	0.9900
5:148338477:GGT:G	acceptor_gain	0.9900
5:148338602:TTAAG:T	donor_loss	0.9900
5:148338604:AA:A	donor_gain	0.9900
5:148338604:AAG:A	donor_loss	0.9900
5:148338605:AGTA:A	donor_loss	0.9900
5:148338606:GTA:G	donor_loss	0.9900
5:148338607:T:A	donor_loss	0.9900
5:148335666:TCA:T	donor_gain	0.9800
5:148335667:CAGT:C	donor_loss	0.9800
5:148335668:AG:A	donor_loss	0.9800

AlphaMissense

575 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:148338550:T:A	C54S	0.982
5:148338551:G:C	C54S	0.982
5:148338592:T:A	C68S	0.977
5:148338593:G:C	C68S	0.977
5:148339707:T:A	C86S	0.977
5:148339708:G:C	C86S	0.977
5:148338590:T:G	F67C	0.976
5:148338526:T:A	C46S	0.974
5:148338527:G:C	C46S	0.974
5:148338484:T:A	C32S	0.970
5:148338485:G:C	C32S	0.970
5:148338579:T:A	N63K	0.968
5:148338579:T:G	N63K	0.968
5:148338578:A:T	N63I	0.966
5:148338583:T:A	C65S	0.963
5:148338584:G:C	C65S	0.963
5:148338554:G:A	G55E	0.962
5:148339709:T:G	C86W	0.961
5:148339707:T:C	C86R	0.957
5:148338590:T:C	F67S	0.953
5:148338585:C:G	C65W	0.952
5:148338593:G:A	C68Y	0.950
5:148338561:T:A	D57E	0.949
5:148338561:T:G	D57E	0.949
5:148338592:T:C	C68R	0.948
5:148338527:G:A	C46Y	0.945
5:148339702:G:T	G84V	0.945
5:148338584:G:A	C65Y	0.944
5:148338526:T:C	C46R	0.942
5:148338551:G:A	C54Y	0.942

dbSNP variants (sampled 300 via entrez): RS1000019494 (5:148329095 G>T), RS1000060844 (5:148325021 A>C), RS1000472348 (5:148322971 A>C), RS1000621643 (5:148331260 G>A), RS1000774662 (5:148323224 A>T), RS1000834990 (5:148330074 C>T), RS1000936020 (5:148329578 G>A,C,T), RS1001056895 (5:148337260 G>A), RS1001171964 (5:148338670 G>A), RS1001451584 (5:148335103 CCT>C), RS1001510322 (5:148319693 T>C), RS1001576232 (5:148328093 G>A), RS1001590027 (5:148325468 T>C), RS1001911823 (5:148328907 G>T), RS1002063424 (5:148325104 T>A)

Disease associations

OMIM: gene MIM:613511 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007611_18	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	1.000000e-13

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

2 total (human), top 2 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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