SPINK5

protein-coding

serine peptidase inhibitor Kazal type 5, the group of Serine peptidase inhibitors, Kazal type

Gene summary

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. [provided by RefSeq, Oct 2015]

MANE transcript

NM_006846.4

Inheritance

ClinVar variants

P:124U:394B:196

Top phenotype

Netherton syndrome

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr5:148,025,683-148,137,382

External References & Databases

Ensembl (ENSG00000133710)

Transcript & Mutation Effects

hg38 • Region Span ~111.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Netherton syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009735

Submitter: ClinGen

Biallelic SPINK5 germline loss-of-function variants were first identified in families with Netherton syndrome (NS) in 2000 (PMID: 10835624). SPINK5 deficiency is associated with a classic clinical triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata (bamboo hair), and severe atopic manifestations. Clinical defects are multisystemic and frequently include life-threatening hypernatremic dehydration in the neonatal period, failure to thrive, severe skin inflammation, enteropathy, and markedly elevated serum IgE levels accompanied by hypereosinophilia and severe allergies. Most curated pathogenic variants are nonsense, frameshift, or splice-site variants predicted to result in loss of function. Multiple unique variants from individuals across multiple publications have been curated (PMID: 11511292, 37102386, 41611084, 24577329). Heterozygous carriers of pathogenic SPINK5 loss-of-function variants do not develop Netherton syndrome. More evidence is available in the literature, but the maximum score for genetic evidence has been reached (12 pts). Studies examining SPINK5 function utilize patient-derived cells and skin biopsy tissues to support this gene-disease relationship. SPINK5 encodes the lympho-epithelial Kazal-type-related inhibitor (LEKTI), a multidomain serine protease inhibitor primarily expressed in the outer granular layer of stratified epithelial tissues. In healthy skin, LEKTI inhibits the activity of epidermal serine proteases, such as kallikreins KLK5, KLK7, and KLK14, which are essential for physiological desquamation and epidermal remodeling (PMID: 17596512). LEKTI has been shown to be expressed in healthy human epidermis but is absent in patients harboring bi-allelic pathogenic SPINK5 variants (PMID:12915442). In vitro functional data demonstrates that this deficiency causes increased epidermal protease hyperactivity, which leads to the premature cleavage of desmosomes, specifically via the rapid degradation of desmoglein (PMID:17989726, 16628198). Mouse models of SPINK5 deficiency replicate the key clinical features of human Netherton syndrome. These animals exhibit altered desquamation, impaired keratinization, hair malformations, severe skin barrier defects, and high postnatal mortality due to dehydration and skin-barrier failure (PMID: 15619623, 38316920). In summary, SPINK5 is definitively associated with autosomal recessive Netherton syndrome. This association is supported by extensive human genetic evidence, functional studies in patient-derived tissues and cells, biochemical data demonstrating LEKTI-dependent inhibition of epidermal kallikreins, and mouse models recapitulating key features of the human disease. This association has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID-CID Working Group on 5/21/2026 (SOP Version 11).

Netherton syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009735

Submitter: Labcorp Genetics (formerly Invitae)

Netherton syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009735

Submitter: PanelApp Australia

Netherton syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009735

Submitter: Genomics England PanelApp

Netherton syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009735

Submitter: G2P

Netherton syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009735

Submitter: Orphanet

Clinical Genomic Database (CGD)

Netherton syndromeAR

Manifestation: Allergy/Immunology/Infectious; Dermatologic

Intervention: Allergy/Immunology/Infectious; Dermatologic

Rationale: The condition may not always be readily recognizable; Recurrent bacterial infections are common, and prophylactic measures, as well as prompt and aggressive treatment of infections may be beneficial; Hypernatremic dehydration in the neonatal period can result in severe sequelae, and awareness may allow preventive measures and prompt medical management

Refs: 13582191; 7822652; 10835624; 11841556; 11693786; 17608759; 19683336; 20107740; 21573681; 21564178; 21692842; 22377713; 22837558; 23331056

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPINK5 variants in ClinVar

10 Conditions Cataloged

Ichthyosis linearis circumflexaTotal: 694

Netherton syndromeTotal: 235

not providedTotal: 196

Inborn genetic diseasesTotal: 130

not specifiedTotal: 100

SPINK5-related disorderTotal: 50

Susceptibility to nonsyndromic otitis mediaTotal: 8

Increased circulating IgE concentrationTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006846.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	11 clinvar	161 clinvar	2 clinvar	175
missense		2 clinvar	379 clinvar	28 clinvar	4 clinvar	413
nonsense	29 clinvar	7 clinvar	1 clinvar			37
start loss			1 clinvar			1
frameshift	37 clinvar	14 clinvar				51
splice donor/acceptor (+/-2bp)	12 clinvar	22 clinvar	2 clinvar	1 clinvar		37
Total	78	46	394	190	6	714

Highest pathogenic variant AF is 0.0002083032

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006846.4	RefSeq	NP_006837.2	33	MANE Select
ENST00000256084.8	Ensembl	ENSP00000256084.7	33	MANE Select
NM_001127698.2	RefSeq	NP_001121170.1	34	Standard
NM_001127699.2	RefSeq	NP_001121171.1	28	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Keratinization
Developmental Biology
Formation of the cornified envelope

Biological Process

negative regulation of antibacterial peptide production
epidermal cell differentiation
negative regulation of angiogenesis
regulation of cell adhesion
extracellular matrix organization

Molecular Function

serine-type endopeptidase inhibitor activity

Cellular Component

extracellular region
cytoplasm
endoplasmic reticulum
endoplasmic reticulum membrane
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359874
Coding exons: 34
Length: 111607
Individuals with no LoFs: 124681
Homozygous LoFs: 1
Heterozygous LoFs: 125
Defined: 124807
p: 0.000505

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.278	562	581	0.967	0.0000310	7326
Missense (PolyPhen)		201	208.61	0.96353		2674
Synonymous	-0.326	185	179	1.03	0.00000908	1825
Loss of Function	2.04	53	71.7	0.740	0.00000410	896

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00058	0.00058	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.0016	0.0016	notable
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00046	0.00046	rare
South Asian	0.00036	0.00036	rare
Other	0.0010	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin. {ECO:0000269|PubMed:10419450, ECO:0000269|PubMed:17596512, ECO:0000269|PubMed:20533828}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:10835624}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.293

Intolerance Scores

LoFtool: 0.997
RVIS EVS: 2.83
RVIS percentile EVS: 99.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0356

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High