GFRA4

Summary

GFRA4 (GDNF family receptor alpha 4, HGNC:13821) is a protein-coding gene on chromosome 20p13, encoding GDNF family receptor alpha-4 (Q9GZZ7). Receptor for persephin (PSPN), a growth factor that exhibits neurotrophic activity on mesencephalic dopaminergic and motor neurons.

The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for persephin, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for RET-associated diseases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 64096 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 57 total
• MANE Select transcript: NM_022139

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13821
Approved symbol	GFRA4
Name	GDNF family receptor alpha 4
Location	20p13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125861
Ensembl biotype	protein_coding
OMIM	618679
Entrez	64096

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 nonsense_mediated_decay

ENST00000290417, ENST00000319242, ENST00000477160, ENST00000850978

RefSeq mRNA: 2 — MANE Select: NM_022139 NM_022139, NM_145762

CCDS: CCDS13055, CCDS13056

Canonical transcript exons

ENST00000290417 — 6 exons

Exon	Start	End
ENSE00000858801	3660158	3660249
ENSE00001044497	3660755	3660864
ENSE00001044498	3660526	3660660
ENSE00001327919	3660944	3661289
ENSE00001642661	3663354	3663399
ENSE00003915460	3659248	3659989

Expression profiles

Bgee: expression breadth broad, 36 present calls, max score 86.83.

Top tissues by expression

272 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	86.83	gold quality
diaphragm	UBERON:0001103	78.80	gold quality
olfactory bulb	UBERON:0002264	67.63	gold quality
type B pancreatic cell	CL:0000169	67.33	gold quality
CA1 field of hippocampus	UBERON:0003881	63.65	gold quality
hair follicle	UBERON:0002073	63.62	gold quality
gluteal muscle	UBERON:0002000	62.52	gold quality
triceps brachii	UBERON:0001509	62.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.57	gold quality
tongue squamous epithelium	UBERON:0006919	60.43	gold quality
left ventricle myocardium	UBERON:0006566	60.38	gold quality
cardiac muscle of right atrium	UBERON:0003379	58.65	gold quality
vastus lateralis	UBERON:0001379	56.73	gold quality
quadriceps femoris	UBERON:0001377	56.54	gold quality
periodontal ligament	UBERON:0008266	56.13	silver quality
inferior olivary complex	UBERON:0002127	55.84	gold quality
cranial nerve II	UBERON:0000941	55.58	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	55.58	gold quality
myocardium	UBERON:0002349	54.58	gold quality
Brodmann (1909) area 46	UBERON:0006483	51.24	gold quality
nasal cavity epithelium	UBERON:0005384	51.17	gold quality
thymus	UBERON:0002370	51.07	gold quality
kidney epithelium	UBERON:0004819	51.00	gold quality
epithelial cell of pancreas	CL:0000083	50.92	gold quality
skin of hip	UBERON:0001554	50.92	silver quality
nephron tubule	UBERON:0001231	50.58	gold quality
cervix squamous epithelium	UBERON:0006922	50.32	gold quality
cervix epithelium	UBERON:0004801	49.83	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
metanephric glomerulus	UBERON:0004736	49.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting GFRA4, 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-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6769B-5P	98.73	64.91	1092

Literature-anchored findings (GeneRIF, showing 4)

• GDNF/GFRalpha1 is crucial for efficient signal transduction to recruit Ret protein into lipid rafts. (PMID:15225646)
• High GFRA4 expression is associated with Hirschsprung’s Disease. (PMID:29090971)
• Results support that aberrant CpG hypermethylation at least partly accounts for GFRA4 silencing in HSCR, which impairs its protective role in enteric nervous system. (PMID:29634418)
• MiR-195-5p inhibits proliferation and invasion of nerve cells in Hirschsprung disease by targeting GFRA4. (PMID:33515383)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfra4a	ENSDARG00000056651
danio_rerio	gfra4b	ENSDARG00000074582
mus_musculus	Gfra4	ENSMUSG00000027316
rattus_norvegicus	Gfra4	ENSRNOG00000021241
drosophila_melanogaster	Gfrl	FBGN0262869
caenorhabditis_elegans		WBGENE00022100

Paralogs (4): GFRA3 (ENSG00000146013), GFRA1 (ENSG00000151892), GFRA2 (ENSG00000168546), GFRAL (ENSG00000187871)

Protein

Protein identifiers

GDNF family receptor alpha-4 — Q9GZZ7 (reviewed: Q9GZZ7)

Alternative names: Persephin receptor

All UniProt accessions (1): Q9GZZ7

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for persephin (PSPN), a 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. May be important in C-cell development and, in the postnatal development of the adrenal medulla.

Subunit / interactions. Interacts with ARTN ligand and RET: forms a 2:2:2 ternary complex composed of ARTN ligand, GFRA3 and RET receptor. Interacts with SORL1.

Subcellular location. Cell membrane Cell membrane Secreted.

Tissue specificity. Predominantly expressed in the adult thyroid gland. Low levels also found in fetal adrenal and thyroid glands.

Similarity. Belongs to the GDNFR family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9GZZ7-1	GFRalpha4b	yes
Q9GZZ7-2	GFRalpha4a
Q9GZZ7-3	GFRalpha4c

RefSeq proteins (2): NP_071422, NP_665705 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003438	GDNF_rcpt	Family
IPR016017	GDNF/GAS1	Domain
IPR037193	GDNF_alpha	Homologous_superfamily

Pfam: PF02351

UniProt features (10 total): splice variant 3, signal peptide 1, chain 1, propeptide 1, region of interest 1, compositionally biased region 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZZ7-F1	69.21	0.42

Functional residue map

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

Post-translational modifications (1): 278

Glycosylation sites (1): 208

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: 59 (showing top): GOCC_CELL_SURFACE, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, WONG_ENDMETRIUM_CANCER_DN, GOBP_OSSIFICATION, GOBP_NEGATIVE_REGULATION_OF_OSSIFICATION, GOBP_REGULATION_OF_OSSIFICATION, GOCC_SIDE_OF_MEMBRANE, GOCC_RECEPTOR_COMPLEX, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_DN, CHEN_METABOLIC_SYNDROM_NETWORK, MARTENS_TRETINOIN_RESPONSE_UP, BRUINS_UVC_RESPONSE_EARLY_LATE

GO Biological Process (4): ossification (GO:0001503), nervous system development (GO:0007399), negative regulation of ossification (GO:0030279), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860)

GO Molecular Function (2): glial cell-derived neurotrophic factor receptor activity (GO:0016167), signaling receptor activity (GO:0038023)

GO Cellular Component (6): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), signaling receptor complex (GO:0043235), membrane (GO:0016020), side of membrane (GO:0098552)

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
cellular anatomical structure	3
membrane	2
multicellular organismal process	1
system development	1
ossification	1
regulation of ossification	1
negative regulation of multicellular organismal process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cytokine receptor activity	1
glial cell-derived neurotrophic factor receptor signaling pathway	1
molecular transducer activity	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
protein-containing complex	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

246 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFRA4	PSPN	O60542	999
GFRA4	ARTN	Q5T4W7	993
GFRA4	NRTN	Q99748	989
GFRA4	GDNF	P39905	978
GFRA4	RET	P07949	855
GFRA4	GFRA3	O60609	552
GFRA4	GFRA1	P56159	523
GFRA4	GFRA2	O00451	500
GFRA4	IL19	Q9UHD0	452
GFRA4	IL9	P15248	432
GFRA4	C10orf120	Q5SQS8	392
GFRA4	JAG1	P78504	390
GFRA4	JAK2	O60674	387
GFRA4	OR10H5	Q8NGA6	370
GFRA4	ATRN	O75882	357

IntAct

0 interactions, top by confidence:

BioGRID (1): GFRA4 (Reconstituted Complex)

ESM2 similar proteins: C9JLR9, D3YZZ2, E1BDF2, E7ERA6, O00110, P0DH78, P29590, P51172, P70225, Q01113, Q02833, Q0VCS0, Q13477, Q13505, Q14626, Q32KV8, Q3UIW8, Q3UV31, Q4R7H0, Q4VA45, Q5R866, Q5RF19, Q5U4P2, Q5VTJ3, Q64385, Q6BAA4, Q6ISU1, Q6ZVT0, Q70EL4, Q7L591, Q86UR1, Q8IYG6, Q8N1F8, Q8N554, Q8NFT6, Q969Z4, Q96G42, Q96HA4, Q96IQ9, Q99640

Diamond homologs: O00451, O08842, O13156, O13157, O35118, O60609, O93512, P56159, P97785, Q5E9X0, Q5RAD6, Q62997, Q9EPI2, Q9GZZ7, Q9JJT2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PSPN	up-regulates	GFRA4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

825 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3660155:TACC:T	donor_loss	1.0000
20:3660246:CCAT:C	acceptor_gain	1.0000
20:3660247:CATC:C	acceptor_gain	1.0000
20:3660250:C:CC	acceptor_gain	1.0000
20:3660538:T:A	donor_gain	1.0000
20:3660245:ACCAT:A	acceptor_gain	0.9900
20:3660246:CCATC:C	acceptor_gain	0.9900
20:3660247:CAT:C	acceptor_gain	0.9900
20:3660249:TC:T	acceptor_loss	0.9900
20:3660250:C:CA	acceptor_loss	0.9900
20:3660251:T:G	acceptor_loss	0.9900
20:3660520:CCTCA:C	donor_loss	0.9900
20:3660521:CTCA:C	donor_loss	0.9900
20:3660522:TCACC:T	donor_loss	0.9900
20:3660523:CAC:C	donor_loss	0.9900
20:3660524:A:AC	donor_gain	0.9900
20:3660524:AC:A	donor_gain	0.9900
20:3660525:C:CC	donor_gain	0.9900
20:3660525:CC:C	donor_gain	0.9900
20:3661383:AAAAC:A	donor_gain	0.9900
20:3660156:A:AC	donor_gain	0.9800
20:3660157:C:CC	donor_gain	0.9800
20:3660157:CCTG:C	donor_gain	0.9800
20:3660538:T:TA	donor_loss	0.9800
20:3660564:T:TA	donor_gain	0.9800
20:3661200:A:AC	donor_gain	0.9800
20:3661201:C:CC	donor_gain	0.9800
20:3663352:AC:A	donor_gain	0.9800
20:3663353:CC:C	donor_gain	0.9800
20:3660571:C:A	donor_gain	0.9700

AlphaMissense

1687 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:3661199:T:C	Y46C	0.998
20:3660546:A:C	F236C	0.997
20:3660605:C:A	W216C	0.996
20:3660605:C:G	W216C	0.996
20:3660558:A:C	F232C	0.995
20:3661034:A:C	F101C	0.995
20:3661124:A:C	F71C	0.995
20:3661082:A:C	F85C	0.994
20:3661121:A:C	F72C	0.994
20:3660545:A:C	F236L	0.993
20:3660545:A:T	F236L	0.993
20:3660547:A:G	F236L	0.993
20:3660641:G:C	N204K	0.993
20:3660641:G:T	N204K	0.993
20:3661015:A:C	F107L	0.993
20:3661015:A:T	F107L	0.993
20:3661017:A:G	F107L	0.993
20:3661123:G:C	F71L	0.993
20:3661123:G:T	F71L	0.993
20:3661124:A:G	F71S	0.993
20:3661125:A:G	F71L	0.993
20:3661220:C:G	C39S	0.993
20:3661221:A:T	C39S	0.993
20:3660567:C:G	C229S	0.992
20:3660567:C:T	C229Y	0.992
20:3660568:A:T	C229S	0.992
20:3661016:A:C	F107C	0.992
20:3661200:A:G	Y46H	0.990
20:3660546:A:G	F236S	0.989
20:3660566:G:C	C229W	0.989

dbSNP variants (sampled 300 via entrez): RS1000089390 (20:3663577 C>G,T), RS1000097171 (20:3661223 C>T), RS1002391556 (20:3665124 A>G), RS1003181983 (20:3660954 G>A), RS1003233187 (20:3660735 C>T), RS1003445712 (20:3663869 A>C), RS1003501161 (20:3663659 C>A), RS1003835687 (20:3663505 G>A,T), RS1003886649 (20:3663228 C>A), RS1003999120 (20:3663823 G>A,C), RS1004121597 (20:3663392 C>G,T), RS1004905193 (20:3662390 A>C), RS1006188932 (20:3664706 C>G), RS1006228690 (20:3664593 A>C,T), RS1006584879 (20:3658891 G>A)

Disease associations

OMIM: gene MIM:618679 | disease phenotypes: MIM:617468, MIM:208150

GenCC curated gene-disease

Mondo (2): arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (2): Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003542_159	Night sleep phenotypes	8.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — GDNF Family Receptor (GFR)

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
propionaldehyde	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Amphotericin B	increases expression	1
Plant Extracts	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3