SPINK5

Summary

SPINK5 (serine peptidase inhibitor Kazal type 5, HGNC:15464) is a protein-coding gene on chromosome 5q32, encoding Serine protease inhibitor Kazal-type 5 (Q9NQ38). Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia.

This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 11005 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Netherton syndrome (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 1,203 total — 89 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 159
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_006846

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15464
Approved symbol	SPINK5
Name	serine peptidase inhibitor Kazal type 5
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	VAKTI, LEKTI, LETKI, NETS, NS, FLJ21544, FLJ97536, FLJ97596, FLJ99794, DKFZp686K19184
Ensembl gene	ENSG00000133710
Ensembl biotype	protein_coding
OMIM	605010
Entrez	11005

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000256084, ENST00000359874, ENST00000398454, ENST00000476608, ENST00000476697, ENST00000481286, ENST00000507988, ENST00000508733, ENST00000521206, ENST00000698105

RefSeq mRNA: 3 — MANE Select: NM_006846 NM_001127698, NM_001127699, NM_006846

CCDS: CCDS43382, CCDS47300, CCDS47301

Canonical transcript exons

ENST00000256084 — 33 exons

Exon	Start	End
ENSE00000910375	148131259	148131389
ENSE00000910376	148126983	148127079
ENSE00000910377	148125723	148125850
ENSE00000910380	148120295	148120391
ENSE00000910381	148120009	148120136
ENSE00000910382	148118986	148119058
ENSE00001032827	148124765	148124837
ENSE00001154656	148133797	148133887
ENSE00001418891	148065347	148065372
ENSE00003461320	148107037	148107164
ENSE00003464536	148114362	148114489
ENSE00003478968	148100454	148100581
ENSE00003489185	148091165	148091228
ENSE00003490118	148089494	148089621
ENSE00003499079	148116370	148116466
ENSE00003510013	148101355	148101436
ENSE00003512476	148108753	148108837
ENSE00003519736	148099234	148099315
ENSE00003544061	148118437	148118564
ENSE00003556260	148070323	148070450
ENSE00003557986	148086405	148086532
ENSE00003566884	148104952	148105000
ENSE00003586045	148101781	148101908
ENSE00003602838	148111768	148111895
ENSE00003627407	148095818	148095905
ENSE00003675481	148097867	148097994
ENSE00003677213	148088542	148088605
ENSE00003686030	148094354	148094481
ENSE00003688650	148072148	148072220
ENSE00003691832	148112868	148112934
ENSE00003784773	148123833	148123960
ENSE00003898555	148136983	148137382
ENSE00003900394	148063980	148064099

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 99.89.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 6.7722 / max 2136.1946, expressed in 125 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59261	6.2335	79
59267	0.1182	44
59268	0.1099	36
59269	0.1099	40
59259	0.0432	2
59271	0.0388	16
59263	0.0310	10
59265	0.0285	10
59270	0.0210	8
59264	0.0166	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tongue squamous epithelium	UBERON:0006919	99.89	gold quality
cervix squamous epithelium	UBERON:0006922	99.78	gold quality
lower esophagus mucosa	UBERON:0035834	99.63	gold quality
mammalian vulva	UBERON:0000997	99.61	gold quality
gingiva	UBERON:0001828	99.57	gold quality
oral cavity	UBERON:0000167	99.56	gold quality
gingival epithelium	UBERON:0001949	99.56	gold quality
upper leg skin	UBERON:0004262	99.56	gold quality
cervix epithelium	UBERON:0004801	99.50	gold quality
pharyngeal mucosa	UBERON:0000355	99.41	gold quality
squamous epithelium	UBERON:0006914	99.40	gold quality
penis	UBERON:0000989	99.31	gold quality
esophagus squamous epithelium	UBERON:0006920	99.21	gold quality
skin of hip	UBERON:0001554	99.07	gold quality
upper arm skin	UBERON:0004263	98.92	gold quality
body of tongue	UBERON:0011876	98.91	gold quality
esophagus mucosa	UBERON:0002469	98.85	gold quality
epithelium of esophagus	UBERON:0001976	98.55	gold quality
skin of abdomen	UBERON:0001416	98.32	gold quality
zone of skin	UBERON:0000014	98.00	gold quality
skin of leg	UBERON:0001511	97.86	gold quality
buccal mucosa cell	CL:0002336	97.59	gold quality
tongue	UBERON:0001723	96.60	gold quality
amniotic fluid	UBERON:0000173	96.22	gold quality
pancreatic ductal cell	CL:0002079	95.94	gold quality
epithelium of nasopharynx	UBERON:0001951	95.24	gold quality
nasopharynx	UBERON:0001728	95.22	gold quality
nipple	UBERON:0002030	94.25	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.18	gold quality
superior surface of tongue	UBERON:0007371	93.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	9517.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting SPINK5, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-6880-5P	98.08	65.59	1282

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• SPINK5’s role in atopic dermatitis and skin diseases is described (PMID:11796258)
• the intron-exon organization of the gene and characterize the spink5 mutations. five mutations, one of which resulted in perinatal lethal disease, were associated with ethnic groups (PMID:11841556)
• the defective inhibitory regulation of desquamation due to SPINK5 gene mutations may cause over-desquamation of corneocytes in Netherton syndrome, leading to severe skin permeability barrier dysfunction. (PMID:11874482)
• This is a multidomain serine proteinase inhibitor with physiopathological significance. (PMID:11943586)
• REVIEW: molecular cloning, characterization of the gene, tissue distribution, congenital disases associated with mutations (PMID:12437098)
• LETKI proteolytic processing was studied in cultured keratinocytes as well as its tissue distribution and defective expression in Netherton syndrome. (PMID:12915442)
• There is an association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. (PMID:14551605)
• LEKTI deficiency in the epidermis and in hair roots at the protein level and an aberrant expression of other proteins, especially transglutaminase1 and 3, which may account for the impaired epidermal barrier in Netherton syndrome (PMID:15304086)
• The sequence from Leu32 to Ile38 of a chimeric double-mutant domain 1 of LEKTI is a chameleon sequence that converts a short 3(10)-helix into an extended loop conformation and parts of the COOH-terminal alpha-helix of domain 1 into a beta-hairpin. (PMID:15366933)
• deficiency is related to epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin (PMID:15466487)
• in normal skin the LG system transports and secretes LEKTI earlier than KLK7 and KLK5 preventing premature loss of stratum corneum integrity/cohesion. (PMID:15675955)
• We showed that LEKTI is a potent inhibitor of a family of serine proteinases involved in extracellular matrix remodeling and its expression is downregulated in head and neck squamous cell carcinomas. (PMID:15680911)
• Homozygous frameshift mutation in SPINK5 associated with Netherton syndrome. (PMID:15942217)
• Variable amounts of SPINK5 alternative transcripts are detected in all SPINK5 transcriptionally active tissues. (PMID:16374478)
• Mutations in SPINK5 encoding the serine protease (SP) inhibitor, lymphoepithelial-Kazal-type 5 inhibitor (LEKTI), cause Netherton syndrome (NS). SP activation correlated with clinical severity, and inversely with residual LEKTI expression. (PMID:16601670)
• Uniparental disomy of maternal SPINK5 allele was indicated in the mutation analysis of two Taiwanese patients with Netherton syndrome. (PMID:17415575)
• These results identify KLK5, a key actor of the desquamation process, as the major target of LEKTI. (PMID:17596512)
• LEKTI domain 15 is a functional Kazal-type proteinase inhibitor. (PMID:17936012)
• SPINK5 mutations, causing NS, lead to truncated LEKTI; each Netherton syndrome patient possesses LEKTI of a different length, depending on the location of mutations (PMID:17989726)
• study in children and adults with atopic dermatitis found that an association with SPINK5 E420K SNP was not confirmed. However, this was associated with high IgE serum levels (p=0.011). (PMID:17989887)
• SPINK5 (LEKTI) protein was detected in sinonasal tissue and was significantly decreased in polyp samples using IHC. (PMID:18588753)
• SPINK5 mutation confers a risk of eczema when maternally inherited but is not a major eczema risk factor; no interaction between the SPINK5 risk allele or the putative KLK7 risk allele and FLG mutations ws found (PMID:18774391)
• reduced expression of LEKTI and increased expression of SCCE and SCTE in human epidermal keratinocytes after UVB irradiation may contribute to desquamation of the stratum corneum. (PMID:19118981)
• Haploinsufficiency of SPINK5 can cause the Netherton syndrome phenotype in the presence of one null mutation with homozygous G1258A polymorphisms in SPINK5, and this could impair the function of LEKTI and therefore acts as a true mutation. (PMID:19438860)
• Even though the number of investigated subjects was small and hydrolytic activity was only slightly increased, the results denote that LEKTI might be diminished in atopic dermatitis (PMID:19522716)
• -206G>A polymorphism in the SPINK5 is associated with asthma susceptibility in a Chinese Han population (PMID:19534795)
• Highly significant associations were detected between SPINK5 single nucleotide polymorphisms and visible eczema (but not IgE levels) and between IL13 variants and total IgE. (PMID:20085599)
• study reports two male siblings affected by Netherton syndrome, which resulted from a previously undescribed splicing mutation in SPINK5 (PMID:20107740)
• Caspase 14 has been implicated as a novel target of LEKTI, which has the potential to act as both a serine and a cysteine protease inhibitor. (PMID:20533828)
• Six SNPs (rs17718511, rs17860502, KN0001820, rs60978485, rs17718737, and rs1422985) and the haplotype TAA (rs60978485, rs6892205, rs2303064) in the SPINK5 gene were associated with atopic dermatitis in Koreans. (PMID:21087323)
• The novel mutation, p.Gln333X, in the SPINK5 gene, is responsible for a mild Netherton syndrome phenotype in a Turkish pedigree. (PMID:21564178)
• the SPINK5 gene polymorphisms was found not to be associated with atopic dermatitis (AD) in regard to either serum IgE levels, concurrent allergic asthma or early onset of AD (PMID:21585560)
• Distinct SPINK5 and IL-31 gene variants (SNPs) were associated with the development of atopic eczema and non-atopic hand dermatitis in Taiwanese nurses. (PMID:22017185)
• New SPINK5 defects in 12 patients, who presented a clinical triad suggestive of Netherton syndrome with variations in inter- and intra-familial disease expression were disclosed. (PMID:22089833)
• Our study represents the first identification of a Netherton disease-causing SPINK5 mutation that alters splicing without affecting canonical splice sites. (PMID:22377713)
• Lowered SPINK5 protein expression might be a contributing factor for the development of chronic rhinosinusitis. (PMID:22570283)
• major binding partners of LEKTI were found to be the antimicrobial peptide dermcidin and the serine protease cathepsin G and no kallikreins. (PMID:22588119)
• The E420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation. (PMID:22730493)
• Herein we report three patients with Netherton syndrome who had growth retardation associated with GH deficiency and responded well to GH therapy. (PMID:24015757)
• mesotrypsin contributes to the desquamation process by activating KLKs and degrading the intrinsic KLKs’ inhibitor LEKTI (PMID:24390132)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spink5	ENSMUSG00000055561
rattus_norvegicus	Spink5	ENSRNOG00000013116

Paralogs (6): FSTL4 (ENSG00000053108), FSTL3 (ENSG00000070404), FST (ENSG00000134363), FSTL1 (ENSG00000163430), FSTL5 (ENSG00000168843), SPINK6 (ENSG00000178172)

Protein

Protein identifiers

Serine protease inhibitor Kazal-type 5 — Q9NQ38 (reviewed: Q9NQ38)

Alternative names: Lympho-epithelial Kazal-type-related inhibitor

All UniProt accessions (4): Q9NQ38, E5RFU9, E5RG22, E7EWP9

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating and desquamation-involved proteases. Inhibits KLK5, its major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in the thymus and stratum corneum. Also found in the oral mucosa, parathyroid gland, Bartholin’s glands, tonsils, and vaginal epithelium. Very low levels are detected in lung, kidney, and prostate.

Post-translational modifications. Proteolytically processed by furin in individual domains (D1, D5, D6, D8 through D11, and D9 through D15) exhibiting various inhibitory potentials for multiple proteases.

Disease relevance. Netherton syndrome (NETH) [MIM:256500] An autosomal recessive congenital ichthyosis associated with hair shaft abnormalities and anomalies of the immune system. Typical features are ichthyosis linearis circumflexa, ichthyosiform erythroderma, trichorrhexis invaginata (bamboo hair), atopic dermatitis, and hayfever. High postnatal mortality is due to failure to thrive, infections and hypernatremic dehydration. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains at least one active inhibitory domain for trypsin (domain 6).

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NQ38-1	f-l	yes
Q9NQ38-2	short
Q9NQ38-3	long

RefSeq proteins (3): NP_001121170, NP_001121171, NP_006837* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00050

UniProt features (102 total): disulfide bond 32, domain 15, sequence variant 13, helix 12, strand 7, region of interest 6, turn 5, compositionally biased region 3, splice variant 3, peptide 2, signal peptide 1, chain 1, site 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1H0Z	SOLUTION NMR
1HDL	SOLUTION NMR
1UUC	SOLUTION NMR
1UVF	SOLUTION NMR
1UVG	SOLUTION NMR
5YHN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQ38-F1	74.37	0.10

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): 46–47 (reactive bond)

Disulfide bonds (32): 30–66, 44–63, 97–133, 111–130, 119–151, 161–197, 175–194, 225–261, 239–258, 297–333, 311–330, 367–403, 381–400, 437–473, 451–470, 496–532, 510–529, 567–603, 581–600, 632–668 …

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-9725554	Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 455 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, E2F_Q4, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, E2F4DP1_01, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, GCANCTGNY_MYOD_Q6, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, GOBP_NEUROGENESIS, AP2_Q3, PRAMOONJAGO_SOX4_TARGETS_DN, CAGCTG_AP4_Q5

GO Biological Process (12): negative regulation of antibacterial peptide production (GO:0002787), epidermal cell differentiation (GO:0009913), negative regulation of angiogenesis (GO:0016525), cell differentiation (GO:0030154), regulation of cell adhesion (GO:0030155), extracellular matrix organization (GO:0030198), epithelial cell differentiation (GO:0030855), hair cell differentiation (GO:0035315), regulation of T cell differentiation (GO:0045580), negative regulation of proteolysis (GO:0045861), negative regulation of immune response (GO:0050777), regulation of timing of anagen (GO:0051884)

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

GO Cellular Component (8): extracellular region (GO:0005576), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cell cortex (GO:0005938), perinuclear region of cytoplasm (GO:0048471), epidermal lamellar body (GO:0097209)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Developmental Biology	2
Keratinization	1
Developmental Cell Lineages of the Integumentary System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	4
antibacterial peptide production	1
negative regulation of antimicrobial peptide production	1
regulation of antibacterial peptide production	1
negative regulation of defense response to bacterium	1
epidermis development	1
epithelial cell differentiation	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cellular developmental process	1
cell adhesion	1
regulation of cellular process	1
extracellular structure organization	1
external encapsulating structure organization	1
cell differentiation	1
epithelium development	1
epidermal cell differentiation	1
neuron differentiation	1
T cell differentiation	1
regulation of lymphocyte differentiation	1
regulation of T cell activation	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
negative regulation of immune system process	1
immune response	1
negative regulation of response to stimulus	1
regulation of immune response	1
anagen	1
regulation of hair follicle maturation	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
intracellular anatomical structure	1
endomembrane system	1

Protein interactions and networks

STRING

1166 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPINK5	ING1	Q9UK53	920
SPINK5	FLG	P20930	916
SPINK5	KLK7	P49862	893
SPINK5	ST14	Q9Y5Y6	881
SPINK5	FLG2	Q5D862	872
SPINK5	KLK4	Q9Y5K2	862
SPINK5	DSG1	Q02413	851
SPINK5	KLK14	Q9P0G3	785
SPINK5	PHF11	Q9UIL8	754
SPINK5	CDSN	Q15517	728
SPINK5	KLK6	Q92876	698
SPINK5	MS4A2	Q01362	635
SPINK5	SPINK6	Q6UWN8	632
SPINK5	SPINK9	Q5DT21	627
SPINK5	ADAM33	Q9BZ11	620

IntAct

15 interactions, top by confidence:

A	B	Type	Score
TFG	CRYAB	psi-mi:“MI:0914”(association)	0.530
SKA2	VSIG8	psi-mi:“MI:0914”(association)	0.530
TEX14	DNAJB6	psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
FSTL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
FOS	GYG2	psi-mi:“MI:0914”(association)	0.350
CSGALNACT1	CTSV	psi-mi:“MI:0914”(association)	0.350
PLD5	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
ISCA2	DUSP14	psi-mi:“MI:0914”(association)	0.350
OLFM4	SPINT1	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
SYT11	PJA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), SPINK5 (Affinity Capture-MS), ALB (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A144LUY5, A0A6B9KZ90, A0A6B9L900, B6DCQ8, C0HJV6, C0HJV7, C0HJV8, D4N4Z9, D6C4I6, O24006, P08724, P0CAZ2, P0CAZ3, P0CAZ4, P0CAZ5, P0CAZ6, P0CAZ7, P0CAZ8, P0CAZ9, P0DSK3, P15216, P15217, P15438, P21250, P34472, P59704, P85247, P85253, P85254, P85255, P85256, P85257, P85258, P85259, P86716, P86717, P86718, P86719, Q1ELU7, Q1ELU8

Diamond homologs: D0MVC9, D0NJ41, O00468, P00995, P05560, P0DKM7, P0DKM8, P0DKM9, P0DKT1, P0DKT2, P0DKT3, P0DKT4, P0DKT5, P11706, P16895, P82968, P85000, Q6PFE7, Q6PQG3, Q6PQH2, Q8IYR6, Q91590, Q9NQ38, Q9QYM9, Q9QYV1, A2ASQ1, A5YT95, D3ZVP0, O35679, O60575, O62650, O95633, P00996, P00997, P00998, P01003, P01005, P04542, P09036, P09655

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1203 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	89
Likely pathogenic	30
Uncertain significance	434
Likely benign	358
Benign	200

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012378	NM_006846.4(SPINK5):c.882+1_882+3del	Pathogenic
1072025	NM_006846.4(SPINK5):c.2038_2039del (p.Lys680fs)	Pathogenic
1072829	NC_000005.9:g.(?147443360)(147484583_?)del	Pathogenic
1254561	NM_006846.4(SPINK5):c.410+1G>A	Pathogenic
1376783	NM_006846.4(SPINK5):c.2472del (p.Glu825fs)	Pathogenic
1379542	NM_006846.4(SPINK5):c.2260A>T (p.Lys754Ter)	Pathogenic
1423328	NM_006846.4(SPINK5):c.679G>T (p.Glu227Ter)	Pathogenic
1448931	NM_006846.4(SPINK5):c.2953_2954del (p.Phe985fs)	Pathogenic
1452231	NM_006846.4(SPINK5):c.1233del (p.Glu412fs)	Pathogenic
1456239	NC_000005.9:g.(?147443608)(147451803_?)del	Pathogenic
1456666	NM_006846.4(SPINK5):c.1732C>T (p.Arg578Ter)	Pathogenic
1460134	NM_006846.4(SPINK5):c.1242_1246del (p.Lys415fs)	Pathogenic
1987697	NM_006846.4(SPINK5):c.2471_2474del (p.Lys824fs)	Pathogenic
2009491	NM_006846.4(SPINK5):c.2483del (p.Asp828fs)	Pathogenic
2025719	NM_006846.4(SPINK5):c.2038_2041del (p.Lys680fs)	Pathogenic
2029653	NM_006846.4(SPINK5):c.695_696del (p.Val232fs)	Pathogenic
2060408	NM_006846.4(SPINK5):c.45C>A (p.Cys15Ter)	Pathogenic
2097455	NM_006846.4(SPINK5):c.1339G>T (p.Gly447Ter)	Pathogenic
2144040	NM_006846.4(SPINK5):c.216del (p.Glu73fs)	Pathogenic
2425647	NC_000005.9:g.(?147470708)(147470811_?)del	Pathogenic
2425648	NC_000005.9:g.(?147443608)(147484583_?)del	Pathogenic
2579630	NM_006846.4(SPINK5):c.941_956del (p.Glu314fs)	Pathogenic
2579679	NM_006846.4(SPINK5):c.715dup (p.Cys239fs)	Pathogenic
265441	NM_006846.4(SPINK5):c.136C>T (p.Gln46Ter)	Pathogenic
2702130	NM_006846.4(SPINK5):c.211G>T (p.Glu71Ter)	Pathogenic
2712648	NM_006846.4(SPINK5):c.2847_2851dup (p.Met951fs)	Pathogenic
2734796	NM_006846.4(SPINK5):c.2039_2049del (p.Lys680fs)	Pathogenic
2734797	NM_006846.4(SPINK5):c.2098G>T (p.Gly700Ter)	Pathogenic
2789176	NM_006846.4(SPINK5):c.829_830del (p.Asp277fs)	Pathogenic
2789920	NM_006846.4(SPINK5):c.666+1G>T	Pathogenic

SpliceAI

4879 predictions. Top by Δscore:

Variant	Effect	Δscore
5:148064098:AGGTG:A	donor_loss	1.0000
5:148064100:G:A	donor_loss	1.0000
5:148070451:G:GG	donor_gain	1.0000
5:148072145:CA:C	acceptor_loss	1.0000
5:148072146:A:AG	acceptor_gain	1.0000
5:148072146:AG:A	acceptor_gain	1.0000
5:148072146:AGG:A	acceptor_gain	1.0000
5:148072146:AGGG:A	acceptor_loss	1.0000
5:148072147:G:GC	acceptor_gain	1.0000
5:148072147:GG:G	acceptor_gain	1.0000
5:148072147:GGG:G	acceptor_gain	1.0000
5:148072147:GGGA:G	acceptor_gain	1.0000
5:148072147:GGGAA:G	acceptor_gain	1.0000
5:148072218:GAG:G	donor_gain	1.0000
5:148086400:TGCA:T	acceptor_loss	1.0000
5:148086401:GCA:G	acceptor_loss	1.0000
5:148086403:A:AG	acceptor_gain	1.0000
5:148086403:AGCT:A	acceptor_gain	1.0000
5:148086404:G:GA	acceptor_gain	1.0000
5:148086404:GC:G	acceptor_gain	1.0000
5:148086404:GCT:G	acceptor_gain	1.0000
5:148086404:GCTG:G	acceptor_gain	1.0000
5:148086404:GCTGA:G	acceptor_gain	1.0000
5:148086528:AATGC:A	donor_gain	1.0000
5:148086529:ATGC:A	donor_gain	1.0000
5:148086530:TGC:T	donor_gain	1.0000
5:148086531:GC:G	donor_gain	1.0000
5:148086531:GCG:G	donor_gain	1.0000
5:148086533:G:GG	donor_gain	1.0000
5:148086533:G:T	donor_loss	1.0000

AlphaMissense

7175 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:148131376:T:A	C1028S	0.995
5:148131377:G:C	C1028S	0.995
5:148089542:T:A	C175S	0.994
5:148089543:G:C	C175S	0.994
5:148089599:T:A	C194S	0.994
5:148089600:G:C	C194S	0.994
5:148089500:T:A	C161S	0.993
5:148089501:G:C	C161S	0.993
5:148131367:T:A	C1025S	0.993
5:148131368:G:C	C1025S	0.993
5:148131271:T:A	C993S	0.992
5:148131272:G:C	C993S	0.992
5:148131310:T:A	C1006S	0.992
5:148131311:G:C	C1006S	0.992
5:148131368:G:A	C1025Y	0.992
5:148131376:T:C	C1028R	0.992
5:148089542:T:C	C175R	0.991
5:148089608:T:A	C197S	0.991
5:148089609:G:C	C197S	0.991
5:148131367:T:C	C1025R	0.991
5:148089599:T:C	C194R	0.990
5:148131310:T:C	C1006R	0.990
5:148131369:C:G	C1025W	0.990
5:148131378:T:G	C1028W	0.990
5:148089500:T:C	C161R	0.989
5:148089595:T:A	N192K	0.989
5:148089595:T:G	N192K	0.989
5:148123839:T:A	C849S	0.989
5:148123840:G:C	C849S	0.989
5:148131377:G:A	C1028Y	0.989

dbSNP variants (sampled 300 via entrez): RS1000017323 (5:148134637 T>C), RS1000073996 (5:148125931 A>G), RS1000108907 (5:148133063 A>C,G), RS1000123490 (5:148127932 A>C), RS1000140068 (5:148080081 T>C), RS1000211818 (5:148108088 C>T), RS1000284379 (5:148120734 C>A), RS1000317979 (5:148087541 A>C,G), RS1000323505 (5:148073212 T>A,C), RS1000369775 (5:148101201 T>C), RS1000397380 (5:148087814 C>A), RS1000457817 (5:148093583 A>G), RS1000461304 (5:148132747 T>C), RS1000543041 (5:148089719 T>C), RS1000549334 (5:148078347 A>T)

Disease associations

OMIM: gene MIM:605010 | disease phenotypes: MIM:256500, MIM:166760

GenCC curated gene-disease

Disease	Classification	Inheritance
Netherton syndrome	Definitive	Autosomal recessive

Mondo (4): ichthyosis linearis circumflexa (MONDO:0043106), Netherton syndrome (MONDO:0009735), exfoliative dermatitis (MONDO:0043233), otitis media, susceptibility to (MONDO:0008162)

Orphanet (1): Netherton syndrome (Orphanet:634)

HPO phenotypes

159 total (30 of 159 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000086	Ectopic kidney
HP:0000126	Hydronephrosis
HP:0000238	Hydrocephalus
HP:0000282	Facial edema
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000498	Blepharitis
HP:0000509	Conjunctivitis
HP:0000653	Sparse eyelashes
HP:0000656	Ectropion
HP:0000737	Irritability
HP:0000952	Jaundice
HP:0000956	Acanthosis nigricans
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001025	Urticaria
HP:0001036	Parakeratosis
HP:0001047	Atopic dermatitis
HP:0001051	Seborrheic dermatitis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001287	Meningitis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_2150	Blood protein levels	3.000000e-09

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003873	Dermatitis, Exfoliative	C17.800.174.318; C17.800.815.318
D056770	Netherton Syndrome	C16.131.077.619; C16.131.831.512.400.705; C16.320.850.673; C16.614.492.400.705; C17.800.428.333.250.705; C17.800.804.512.400.705; C17.800.827.655

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2303070	SPINK5		0.00	0

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases abundance, decreases reaction, increases expression, decreases expression, increases abundance (+1 more)	4
Benzo(a)pyrene	increases mutagenesis, increases expression, increases methylation	3
Valproic Acid	affects expression, decreases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression	2
TAK-243	increases sumoylation	1
trichostatin A	increases expression	1
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases reaction, increases expression	1
(+)-JQ1 compound	decreases expression	1
Microplastics	decreases expression, increases abundance	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Allergens	increases expression, affects cotreatment, decreases abundance	1
Vehicle Emissions	affects cotreatment, decreases abundance, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Furaldehyde	affects cotreatment, increases expression	1
Polystyrenes	decreases expression, increases abundance	1
Progesterone	affects cotreatment, increases expression	1
Silicon Dioxide	increases expression	1
Sodium Chloride	increases expression, affects cotreatment	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Aflatoxin B1	increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1WU	SAHGMUi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02113904	PHASE2	COMPLETED	Clinical Trial Using Humira in Netherton Syndrome
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT01428297	PHASE1	COMPLETED	A Study Evaluating the Safety and Efficacy of Topical BPR277 for the Treatment of Atopic Dermatitis and Netherton Syndrome
NCT01545323	PHASE1	UNKNOWN	Gene Therapy for Netherton Syndrome
NCT05388903	PHASE1	COMPLETED	A Study to Assess the Safety and Pharmacokinetics of Single Ascending Subcutaneous and Intravenous Doses of DS-2325a in Healthy Subjects
NCT05583669	PHASE1	COMPLETED	A Study to Assess the Safety and Pharmacokinetics of Multiple Ascending Subcutaneous Doses of DS-2325a in Healthy Subjects
NCT06137157	PHASE1	RECRUITING	Evaluation of Topical ATR12-351 in Adults With Netherton Syndrome
NCT06539507	PHASE1	RECRUITING	A Study of the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of BCX17725
NCT04244006	PHASE2/PHASE3	UNKNOWN	A Pilot Study of the Efficacy and Safety of Dupilumab Versus Placebo in Patients With Netherton Syndrome
NCT05521438	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Safety, Tolerability and Efficacy of QRX003 Lotion in Subjects With Netherton Syndrome
NCT05789056	PHASE2/PHASE3	RECRUITING	Open Label, Safety and Efficacy Study of QRX003 Lotion in Subjects With Netherton Syndrome
NCT05856526	PHASE2/PHASE3	TERMINATED	A Study to Test Whether Spesolimab Helps People With a Skin Disease Called Netherton Syndrome
NCT06953466	PHASE2/PHASE3	RECRUITING	Clinical Study of QRX003 Lotion in Subjects With Netherton Syndrome
NCT07538583	PHASE2/PHASE3	RECRUITING	Phase 2/3 Clinical Study of QRX003 Lotion in Subjects With Netherton Syndrome
NCT00208026	PHASE1/PHASE2	COMPLETED	Safety Study of Elidel (Pimecrolimus) 1% Cream to Treat Netherton Syndrome
NCT05211830	PHASE1/PHASE2	COMPLETED	A Study to Evaluate Topically Applied SXR1096 Cream in Patients With Netherton Syndrome
NCT05979831	PHASE1/PHASE2	TERMINATED	A Study to Explore Safety, Pharmacokinetics, and Early Clinical Signal of Efficacy of DS-2325a in Patients With Netherton Syndrome
NCT02081313	Not specified	COMPLETED	Natural History and Biological Study of Netherton Syndrome
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT05902663	Not specified	TERMINATED	Natural History of Netherton Syndrome
NCT07280091	Not specified	NOT_YET_RECRUITING	Study of Skin and Gut Microbiome in a Skin Condition Involving Skin Barrier Impairment and Allergic Symptoms: Netherton Syndrome