PSPN

Summary

PSPN (persephin, HGNC:9579) is a protein-coding gene on chromosome 19p13.3, encoding Persephin (O60542). Growth factor that exhibits neurotrophic activity on mesencephalic dopaminergic and motor neurons.

This gene encodes a secreted ligand of the GDNF (glial cell line-derived neurotrophic factor) subfamily and TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate the mature protein. This protein signals through the RET receptor tyrosine kinase and a GPI-linked coreceptor, and promotes survival of neuronal populations. This protein may play a role in cell death, and nervous system development and function. Elevated expression of this gene has been observed in oral squamous cell carcinoma.

Source: NCBI Gene 5623 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_004158

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9579
Approved symbol	PSPN
Name	persephin
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	PSP
Ensembl gene	ENSG00000125650
Ensembl biotype	protein_coding
OMIM	602921
Entrez	5623

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000245810, ENST00000597721

RefSeq mRNA: 1 — MANE Select: NM_004158 NM_004158

CCDS: CCDS12164

Canonical transcript exons

ENST00000245810 — 2 exons

Exon	Start	End
ENSE00000666075	6375702	6375933
ENSE00000857445	6375148	6375616

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 78.38.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.38	silver quality
tendon of biceps brachii	UBERON:0008188	77.38	gold quality
sperm	CL:0000019	71.96	silver quality
cortical plate	UBERON:0005343	71.38	gold quality
male germ cell	CL:0000015	71.17	gold quality
mucosa of transverse colon	UBERON:0004991	70.60	gold quality
pancreatic ductal cell	CL:0002079	69.64	silver quality
ventricular zone	UBERON:0003053	68.80	gold quality
stromal cell of endometrium	CL:0002255	68.58	gold quality
ganglionic eminence	UBERON:0004023	67.93	gold quality
buccal mucosa cell	CL:0002336	66.78	silver quality
cerebellar hemisphere	UBERON:0002245	66.75	gold quality
cerebellar cortex	UBERON:0002129	66.69	gold quality
right hemisphere of cerebellum	UBERON:0014890	66.49	gold quality
type B pancreatic cell	CL:0000169	65.98	gold quality
granulocyte	CL:0000094	65.18	gold quality
cerebellum	UBERON:0002037	65.04	gold quality
embryo	UBERON:0000922	64.32	gold quality
diaphragm	UBERON:0001103	64.09	gold quality
right frontal lobe	UBERON:0002810	63.32	gold quality
prefrontal cortex	UBERON:0000451	62.86	gold quality
anterior cingulate cortex	UBERON:0009835	62.49	gold quality
cingulate cortex	UBERON:0003027	62.48	gold quality
oviduct epithelium	UBERON:0004804	62.02	gold quality
cartilage tissue	UBERON:0002418	61.79	gold quality
blood	UBERON:0000178	61.78	gold quality
right lobe of liver	UBERON:0001114	61.75	gold quality
lower esophagus mucosa	UBERON:0035834	61.73	gold quality
islet of Langerhans	UBERON:0000006	61.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	60.94	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, ETS2

Literature-anchored findings (GeneRIF, showing 5)

• Persephin/GFRalpha4 is unable to recruit RET protein into lipid rafts. (PMID:15225646)
• The results obtained suggest the involvement of NTN, PSP, and ART in processes subserving both the organization of this cortical region during development and the functional activity and maintenance of the mature human hippocampal neurons. (PMID:15829225)
• No differences were found in the allelic frequencies of the variants or in the haplotype distribution between Hirschsprung’s disease patients & controls, nor to any demographic/clinical parameters within the group of patients. (PMID:18970938)
• Results identify persephin, a GDNF family member, as a novel ligand for GFRalpha1/RET receptor complex. (PMID:20350599)
• Results suggested that PSPN is a possible key regulator of oral squamous cell carcinoma (OSCC) progression via PSPN-RET-mitogen-activated protein kinase activation and that PSPN overexpression may have diagnostic potential for OSCC. (PMID:24375483)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000111946
mus_musculus	Pspn	ENSMUSG00000002664
rattus_norvegicus	Pspn	ENSRNOG00000081220

Paralogs (3): ARTN (ENSG00000117407), GDNF (ENSG00000168621), NRTN (ENSG00000171119)

Protein

Protein identifiers

Persephin — O60542 (reviewed: O60542)

All UniProt accessions (2): O60542, M0QYK2

UniProt curated annotations — full annotation on UniProt →

Function. Growth factor that exhibits neurotrophic activity on mesencephalic dopaminergic and motor neurons. Acts by binding to its coreceptor, GFRA4, leading to autophosphorylation and activation of the RET receptor.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with GFRA4 coreceptor and RET: forms a 2:2:2 ternary complex composed of PSPN ligand, GFRA4 and RET receptor.

Subcellular location. Secreted.

Similarity. Belongs to the TGF-beta family. GDNF subfamily.

RefSeq proteins (1): NP_004149* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001839	TGF-b_C	Domain
IPR029034	Cystine-knot_cytokine	Homologous_superfamily
IPR043401	GDNF_fam	Family

Pfam: PF00019

UniProt features (6 total): disulfide bond 4, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60542-F1	78.72	0.52

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (4): 66–124, 93–152, 97–154, 123

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-419037	NCAM1 interactions
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8853659	RET signaling

MSigDB gene sets: 66 (showing top): REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_CELL_PROJECTION_ORGANIZATION, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY, chr19p13, GOMF_GROWTH_FACTOR_RECEPTOR_BINDING, GOMF_KINASE_BINDING, GOMF_PROTEIN_TYROSINE_KINASE_BINDING, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, TGATTTRY_GFI1_01, MIKKELSEN_MCV6_LCP_WITH_H3K4ME3, MIKKELSEN_MEF_LCP_WITH_H3K4ME3

GO Biological Process (5): nervous system development (GO:0007399), central nervous system development (GO:0007417), peripheral nervous system development (GO:0007422), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860), system development (GO:0048731)

GO Molecular Function (4): signaling receptor binding (GO:0005102), growth factor activity (GO:0008083), glial cell-derived neurotrophic factor receptor binding (GO:0030116), receptor tyrosine kinase binding (GO:0030971)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
NCAM signaling for neurite out-growth	1
MAPK1/MAPK3 signaling	1
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	3
nervous system development	2
cell surface receptor protein tyrosine kinase signaling pathway	1
multicellular organism development	1
anatomical structure development	1
protein binding	1
receptor ligand activity	1
growth factor receptor binding	1
signaling receptor binding	1
protein tyrosine kinase binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSPN	GFRA4	Q9GZZ7	999
PSPN	GFRA1	P56159	998
PSPN	GFRA3	O60609	997
PSPN	GFRA2	O00451	994
PSPN	RET	P07949	994
PSPN	GFRAL	Q6UXV0	797
PSPN	NTRK1	P04629	769
PSPN	GDNF	P39905	745
PSPN	NRTN	Q99748	704
PSPN	ARTN	Q5T4W7	675
PSPN	SDC3	O75056	578
PSPN	NTF4	P34130	575
PSPN	CDNF	Q49AH0	568
PSPN	NTF3	P20783	554
PSPN	PROK1	P58294	507

IntAct

2 interactions, top by confidence:

A	B	Type	Score
PSPN	ACTA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): GFRA4 (Reconstituted Complex), PSPN (Reconstituted Complex), KLHL3 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), MVB12A (Affinity Capture-MS)

ESM2 similar proteins: A5A8Y8, D4AB34, O08717, O09108, O60542, O70300, O70301, O77755, O77805, O77835, O88959, P01230, P01232, P03972, P04087, P05111, P07434, P07994, P17490, P18842, P27106, P34820, P38440, P43031, P49000, P55101, P55103, P58166, P79295, P97463, Q04997, Q3SWY4, Q5SZI1, Q5T4W7, Q6AYE8, Q6IY74, Q6PGN1, Q76LW6, Q7Z5Y6, Q8HZR9

Diamond homologs: O60542, O70300, O70301, P39905, P48540, P97463, Q06PM8, Q07731, Q5T4W7, Q6AYE8, Q98TU0, Q99748, Q9Z0L2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PSPN	up-regulates	GFRA4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

102 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6375700:AC:A	donor_gain	1.0000
19:6375701:CC:C	donor_gain	1.0000
19:6375696:CCTTA:C	donor_loss	0.9900
19:6375697:CTTAC:C	donor_loss	0.9900
19:6375698:TTACC:T	donor_loss	0.9900
19:6375699:TA:T	donor_loss	0.9900
19:6375700:A:AC	donor_gain	0.9900
19:6375700:A:AG	donor_loss	0.9900
19:6375701:C:CC	donor_gain	0.9900
19:6375701:C:CG	donor_loss	0.9900
19:6375701:CCCAG:C	donor_gain	0.9900
19:6375617:C:CC	acceptor_gain	0.9500
19:6375614:TGCCT:T	acceptor_loss	0.9400
19:6375615:GCCT:G	acceptor_loss	0.9400
19:6375616:CCTG:C	acceptor_loss	0.9400
19:6375618:T:A	acceptor_loss	0.9400
19:6375704:AG:A	donor_gain	0.9300
19:6375614:TGC:T	acceptor_gain	0.9200
19:6375695:T:TA	donor_gain	0.9200
19:6375748:T:A	donor_gain	0.9100
19:6375715:T:TA	donor_gain	0.9000
19:6375726:C:CT	donor_loss	0.9000
19:6375615:GC:G	acceptor_gain	0.8800
19:6375616:CC:C	acceptor_gain	0.8800
19:6375612:GGTGC:G	acceptor_gain	0.8700
19:6375701:CCCA:C	donor_gain	0.8700
19:6375712:C:A	donor_gain	0.8700
19:6375613:GTGC:G	acceptor_gain	0.8300
19:6375705:G:C	donor_gain	0.8300
19:6375700:ACC:A	donor_gain	0.8200

AlphaMissense

956 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6375364:A:C	F134C	0.994
19:6375363:G:C	F134L	0.993
19:6375363:G:T	F134L	0.993
19:6375365:A:G	F134L	0.993
19:6375496:A:C	F90C	0.993
19:6375342:C:A	W141C	0.991
19:6375342:C:G	W141C	0.991
19:6375364:A:G	F134S	0.989
19:6375496:A:G	F90S	0.988
19:6375487:C:T	C93Y	0.974
19:6375495:G:C	F90L	0.972
19:6375495:G:T	F90L	0.972
19:6375497:A:G	F90L	0.972
19:6375487:C:G	C93S	0.971
19:6375488:A:T	C93S	0.971
19:6375486:G:C	C93W	0.969
19:6375491:A:C	Y92D	0.968
19:6375358:T:A	D136V	0.963
19:6375508:T:A	E86V	0.962
19:6375388:G:T	P126H	0.959
19:6375359:C:G	D136H	0.958
19:6375379:T:C	Y129C	0.954
19:6375482:C:A	G95C	0.953
19:6375487:C:A	C93F	0.953
19:6375394:C:G	C124S	0.951
19:6375395:A:T	C124S	0.951
19:6375310:C:T	C152Y	0.950
19:6375344:A:G	W141R	0.946
19:6375344:A:T	W141R	0.946
19:6375357:A:C	D136E	0.945

dbSNP variants (sampled 300 via entrez): RS1000359758 (19:6374657 CT>C), RS1001622519 (19:6377824 G>T), RS1002298396 (19:6375623 G>A), RS1002576743 (19:6376677 C>A,T), RS1002585074 (19:6376931 G>A), RS1006466438 (19:6375352 C>G,T), RS1006822863 (19:6377221 G>A), RS1007151474 (19:6377153 C>T), RS1007897446 (19:6376211 C>G,T), RS1008232520 (19:6376198 C>T), RS1009879215 (19:6374877 C>A,T), RS1011757498 (19:6376449 G>A), RS1013228017 (19:6374708 T>C), RS1014478882 (19:6377835 G>A), RS1016089366 (19:6374774 C>T)

Disease associations

OMIM: gene MIM:602921 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	decreases methylation	1
Copper	affects binding, decreases expression	1
Disulfiram	affects binding, decreases expression	1
Endosulfan	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Smoke	increases expression, increases abundance	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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