PSTPIP1

protein-coding

proline-serine-threonine phosphatase interacting protein 1, the group of F-BAR domain containing

Gene summary

This gene encodes a cytoskeletal protein that is highly expressed in hemopoietic tissues. This protein functions via its interaction with several different proteins involved in cytoskeletal organization and inflammatory processes. It binds to the cytoplasmic tail of CD2, an effector of T cell activation and adhesion, downregulating CD2-triggered adhesion. It binds PEST-type protein tyrosine phosphatases (PTP) and directs them to c-Abl kinase to mediate c-Abl dephosphorylation, thereby, regulating c-Abl activity. It also interacts with pyrin, which is found in association with the cytoskeleton in myeloid/monocytic cells and modulates immunoregulatory functions. Mutations in this gene are associated with PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. It is hypothesized that the disease-causing mutations compromise physiologic signaling necessary for the maintenance of a proper inflammatory response. [provided by RefSeq, Mar 2016]

MANE transcript

NM_003978.5

Inheritance

ClinVar variants

P:5U:350B:193

Top phenotype

Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne;

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr15:76,993,359-77,037,475

External References & Databases

Ensembl (ENSG00000140368)

Transcript & Mutation Effects

hg38 • Region Span ~44.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autoinflammatory syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019751

Submitter: Ambry Genetics

pyogenic arthritis-pyoderma gangrenosum-acne syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011462

Submitter: G2P

pyogenic arthritis-pyoderma gangrenosum-acne syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011462

Submitter: Labcorp Genetics (formerly Invitae)

hyperzincemia with functional zinc depletionSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011174

Submitter: PanelApp Australia

pyogenic arthritis-pyoderma gangrenosum-acne syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011462

Submitter: PanelApp Australia

pyogenic arthritis-pyoderma gangrenosum-acne syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011462

Submitter: Orphanet

recurrent infections-inflammatory syndrome due to zinc metabolism disorder syndromeSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0016676

Submitter: Orphanet

Clinical Genomic Database (CGD)

Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne; AD

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Endocrine; Musculoskeletal

Intervention: Allergy/Immunology/Infectious; Dermatologic; Endocrine; Hematologic; Musculoskeletal

Rationale: Medical treatment (eg, anakinra) can be effective to treat autoimmune manifestations; Cytopenia related to sulfonamide use has been reported

Comments: Allergy/Immunology/Infectious; Pharmacogenomic

Refs: Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia may involve recurrent infections, and awareness may allow preventative measures and early and aggressive treatment of infections; Medical management has been described as beneficial in some individuals; In Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, medical treatment (eg, anakinra) can be effective to treat autoimmune manifestations; Cytopenia related to sulfonamide use has been reported

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSTPIP1 variants in ClinVar

8 Conditions Cataloged

Pyogenic arthritis-pyoderma gangrenosum-acne syndromeTotal: 661

not providedTotal: 184

not specifiedTotal: 120

Inborn genetic diseasesTotal: 71

Autoinflammatory syndromeTotal: 70

PSTPIP1-related disorderTotal: 27

Hyperzincemia and hypercalprotectinemiaTotal: 6

Behcet diseaseTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003978.5. 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			9 clinvar	153 clinvar	1 clinvar	163
missense	4 clinvar		301 clinvar	37 clinvar	1 clinvar	343
nonsense			13 clinvar			13
start loss						0
frameshift			15 clinvar			15
splice donor/acceptor (+/-2bp)		1 clinvar	12 clinvar	1 clinvar		14
Total	4	1	350	191	2	548

Highest pathogenic variant AF is 0.000012620579

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003978.5	RefSeq	NP_003969.2	15	MANE Select
ENST00000558012.6	Ensembl	ENSP00000452746.1	15	MANE Select
NM_001321135.2	RefSeq	NP_001308064.1	14	Standard
NM_001321136.2	RefSeq	NP_001308065.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOD-like receptor signaling pathway - Homo sapiens (human)
T-Cell antigen Receptor (TCR) Signaling Pathway
The NLRP3 inflammasome
Inflammasomes
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways

Biological Process

endocytosis
inflammatory response
cell adhesion
signal transduction
actin filament polymerization

Molecular Function

protein binding
cytoskeletal protein binding
identical protein binding
actin filament binding

Cellular Component

uropod
cytoplasm
cytosol
cytoskeleton
actin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000558012
Coding exons: 15
Length: 43974
Individuals with no LoFs: 124457
Homozygous LoFs: 1
Heterozygous LoFs: 79
Defined: 124537
p: 0.000321

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.917	215	256	0.839	0.0000167	2652
Missense (PolyPhen)		48	65.336	0.73467		631
Synonymous	-0.931	121	109	1.11	0.00000770	760
Loss of Function	2.55	14	28.8	0.487	0.00000141	309

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00015	0.00014	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.0015	0.0015	notable
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell:APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation (By similarity). Down-regulates CD2-stimulated adhesion through the coupling of PTPN12 to CD2. Also has a role in innate immunity and the inflammatory response. Recruited to inflammasomes by MEFV. Induces formation of pyroptosomes, large supramolecular structures composed of oligomerized PYCARD dimers which form prior to inflammatory apoptosis. Binding to MEFV allows MEFV to bind to PYCARD and facilitates pyroptosome formation. Regulates endocytosis and cell migration in neutrophils. {ECO:0000250, ECO:0000269|PubMed:17964261, ECO:0000269|PubMed:18480402, ECO:0000269|PubMed:19109554, ECO:0000269|PubMed:19584923, ECO:0000269|PubMed:9857189}.;
Disease: DISEASE: PAPA syndrome (PAPAS) [MIM:604416]: Characterized by autosomal dominant inheritance of early-onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction. {ECO:0000269|PubMed:11971877, ECO:0000269|PubMed:14595024, ECO:0000269|PubMed:22161697}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.172

Intolerance Scores

LoFtool: 0.794
RVIS EVS: 0.31
RVIS percentile EVS: 72.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.671

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium