GDNF

Summary

GDNF (glial cell derived neurotrophic factor, HGNC:4232) is a protein-coding gene on chromosome 5p13.2, encoding Glial cell line-derived neurotrophic factor (P39905). Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The recombinant form of this protein, a highly conserved neurotrophic factor, was shown to promote the survival and differentiation of dopaminergic neurons in culture, and was able to prevent apoptosis of motor neurons induced by axotomy. This protein is a ligand for the product of the RET (rearranged during transfection) protooncogene. Mutations in this gene may be associated with Hirschsprung disease and Tourette syndrome. This gene encodes multiple protein isoforms that may undergo similar proteolytic processing.

Source: NCBI Gene 2668 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hirschsprung disease, susceptibility to, 3 (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 212 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 32
• Transcription factor: yes — 18 downstream targets (CollecTRI)
• MANE Select transcript: NM_000514

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4232
Approved symbol	GDNF
Name	glial cell derived neurotrophic factor
Location	5p13.2
Locus type	gene with protein product
Status	Approved
Aliases	ATF1, ATF2, HFB1-GDNF
Ensembl gene	ENSG00000168621
Ensembl biotype	protein_coding
OMIM	600837
Entrez	2668

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000326524, ENST00000344622, ENST00000381826, ENST00000427982, ENST00000502572, ENST00000510177, ENST00000515058, ENST00000620847, ENST00000854000

RefSeq mRNA: 5 — MANE Select: NM_000514 NM_000514, NM_001190468, NM_001190469, NM_001278098, NM_199231

CCDS: CCDS3922, CCDS3923, CCDS54845, CCDS54846, CCDS75237

Canonical transcript exons

ENST00000326524 — 3 exons

Exon	Start	End
ENSE00001249157	37839507	37840041
ENSE00001829583	37812677	37816135
ENSE00003465501	37834646	37834822

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 93.77.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2212 / max 73.8166, expressed in 85 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61339	0.0906	28
61340	0.0662	16
61341	0.0577	12
61342	0.0067	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	93.77	gold quality
tibialis anterior	UBERON:0001385	86.07	silver quality
deltoid	UBERON:0001476	77.78	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	77.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	77.19	gold quality
gastrocnemius	UBERON:0001388	77.16	gold quality
muscle of leg	UBERON:0001383	76.48	gold quality
biceps brachii	UBERON:0001507	74.45	gold quality
skeletal muscle tissue	UBERON:0001134	74.36	gold quality
muscle tissue	UBERON:0002385	73.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	73.34	gold quality
lower esophagus	UBERON:0013473	73.25	gold quality
quadriceps femoris	UBERON:0001377	72.92	silver quality
mucosa of stomach	UBERON:0001199	72.57	gold quality
ileal mucosa	UBERON:0000331	71.57	gold quality
vastus lateralis	UBERON:0001379	71.12	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	70.49	gold quality
smooth muscle tissue	UBERON:0001135	69.67	gold quality
colon	UBERON:0001155	69.62	gold quality
large intestine	UBERON:0000059	69.10	gold quality
cardiac muscle of right atrium	UBERON:0003379	68.63	gold quality
transverse colon	UBERON:0001157	68.24	gold quality
left ventricle myocardium	UBERON:0006566	67.90	gold quality
rectum	UBERON:0001052	67.67	gold quality
intestine	UBERON:0000160	67.37	gold quality
sperm	CL:0000019	67.08	gold quality
kidney epithelium	UBERON:0004819	66.94	gold quality
stromal cell of endometrium	CL:0002255	65.98	gold quality
pancreatic ductal cell	CL:0002079	65.84	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.58

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

18 targets.

Target	Regulation
ALCAM	Activation
BIN1	Activation
CLU	Activation
DCX	Repression
DNM2	Repression
FST	Activation
ID1	Activation
ID2	Activation
ID3	Activation
LAMA3	Activation
MAP1LC3B	Activation
NRG1	Activation
NRN1	Activation
PAFAH1B1	Repression
PDPK1	Activation
PTK2	Activation
RHOQ	Activation
TUBA1A	Repression

Upstream regulators (CollecTRI, top): APEX1, BCL6B, CEBPA, CEBPB, EGR1, KLF10, NEUROD1, NFKB1, NFKB, NR5A1, PAX2, PITX3, POU3F1, RARA, SIX2, SIX4, TFAP2A, TLX1, WT1, ZKSCAN7, ZNF256, ZNF91

miRNA regulators (miRDB)

220 targeting GDNF, 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-5193	100.00	67.26	1744
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• a candidate modifier in a type 1 neurofibromatosis (NF1) enteric phenotype (PMID:11565554)
• GDNF and NRTN are new neuromodulators that regulate the development of the neuromuscular synapse (PMID:11790765)
• Two GDNF mutations identified in Hirschsprung disease patients have reduced binding affinity for the receptor (PMID:11823451)
• GDNF may play a role in the development of intrahippocampal circuitry and in neuronal function and maintenance throughout life. (PMID:11844480)
• GDNF mRNA-containing neurons were found in normal neonate and adult human hippocampus. The data suggest a role for GDNF in neuronal function throughout life. (PMID:11844483)
• Hirschsprung associated GDNF mutations do not prevent RET activation (PMID:11973622)
• The gene expression of this protein was studied in the developing human tooth. (PMID:12397373)
• involvement of heparan sulphate glycosaminoglycan in GDNF signalling (PMID:12414995)
• GDNF upregulates expression and enzymatic activity of MMP-9 through different signaling pathways. GDNF modulates MMP-9 expression and activation, and this may promote pancreatic cancer invasion. (PMID:12947332)
• This study have performed, in an Italian sample, an association study on 3’ UTR (AGG)n repeat in GDNF gene. Our results have evidenced a difference in the allele frequencies between patients and controls. (PMID:15003293)
• GDNF over-expression in myo-GDNF transgenic mice enhances reinnervation, but at the expense of both neurofilament integrity and functional reliability. (PMID:15106825)
• A locally delivered human GDNF-expressing lentiviral vector allows partial protection of motoneurons in the facial nucleus of SOD1(G93A) transgenic mice, whereas it does not prevent loss in the spinal cord. (PMID:15207271)
• GDNF promotes NF-kappaB activation and that the latter is involved in the invasive potential of human pancreatic cancer cells. (PMID:15211107)
• Among the genes upregulated by GDNF were many genes involved in early mammalian development, differentiation, and the cell cycle. (PMID:15708562)
• Intrastriatal lentiviral vector transfer of GDNF, performed at 5 weeks of age, does not ameliorate neurological and behavioral impairments in the R6/2 transgenic mice model of Huntington disease. (PMID:15817265)
• GDNF is overexpressed at the transcript level in squamous non-small-cell lung carcinoma (PMID:15870700)
• Addition of GDNF to activated peripheral blood mononuclear leukocytes reduces the amount of detectable tumor necrosis factor protein without altering its transcription. (PMID:16081799)
• Thus, our findings suggest a role for GDNF signaling in promoting resistance to differentiation or cytotoxic therapy of neuroblastoma, and, preclude their use in this neural crest tumor. (PMID:16125842)
• Transgene GDNF in transgenic astrocytes significantly upregulates c-Jun expression in naive motoneurons (MNs), further upregulates injury-induced c-Jun expression in facial MNs, and results in its activation in most surviving MNs. (PMID:16497298)
• Taken together, our results suggest that SH2-Bbeta is a new signaling molecule involved in GDNF-induced neurite outgrowth. (PMID:16569669)
• Loss of dopaminergic neurons in the substantia nigra may induce changes in the expression of GDNF but not its receptor snd Parkinson disease. (PMID:16644101)
• Results suggest that Dok-4, through activation of the Rap1-ERK1/2 pathway, regulates GDNF-mediated neurite outgrowth during neuronal development. (PMID:16820412)
• GDNF and neurturin differentially regulate the expression of distinct miRNA precursors through the activation of mitogen-activated protein kinase (PMID:16895582)
• GDNF-mediated, autoregulatory long-lasting feedback loop could have important implications for GDNF’s potential value as a treatment for addiction and neurodegenerative diseases. (PMID:17023388)
• The role of heparin and heparan sulfate in GDNF signalling remains unclear, but the present study indicates that it does not occur in the first step of the pathway, namely GDNF-GFRalpha1 engagement. (PMID:17298301)
• Glial cell-derived cytokines such as GDNF and VEGF regulate the blood retinal barrier, implying that glial cell can be a possible therapeutic target in diabetic retinopathy. (PMID:17470563)
• These findings provide evidence for a novel cooperative interaction between VEGFR2 and RET that mediates VEGF-A functions in ureteric bud cells. (PMID:17490619)
• GDNF may promote or inhibit neurite outgrowth through the multicomponent receptor complex, depending on the brain’s expressions of specific GDNF family GFR alpha 2 receptor spliced isoforms. (PMID:17522305)
• To test if GDNF is a susceptibility gene for schizophrenia, we performed a detailed association study. We chose 9 SNPs that spanned a genomic region of 40 kb and fully encompassed GDNF. SNPs were genotyped in a sample of 673 schizophrenic patients. (PMID:17897812)
• These data suggest that gene transfer of Gdnf should be considered as a component of therapy for retinal degenerations in which oxidative damage plays a role. (PMID:17935603)
• These findings suggest that BMZF3 is a transcriptional repressor induced by GDNF that plays a role in cell proliferation. (PMID:18060868)
• GDNF, NTN, GFRalpha-1, GFRalpha-2, and c-Ret proteins are differentially expressed in the different stages of hair follicle cycle. GFRalpha-mediated signaling involves c-Ret and may play a role in human HF biology. (PMID:18222320)
• Data show that reduced expression levels of GDNF mRNAs are found in patients with major depressive disorder in a current depressive state, but not in a remissive state. (PMID:18313696)
• GDNF reverses this ethanol-mediated adaptation by inhibiting the interaction of tyrosine hydroxylase with HSP90. (PMID:18343820)
• direct receptor-receptor interactions are not required for high affinity GDNF binding to NCAM but play an important role in the regulation of NCAM-mediated cell adhesion by GFRalpha1 (PMID:18353777)
• Results describe the relationship between overexpression of glial cell-derived neurotrophic factor and its RET receptor with progression and prognosis of human pancreatic cancer. (PMID:18652760)
• analysis of how GDNF.GFR alpha 1 can mediate cell adhesion and how heparin might inhibit GDNF signaling through RET (PMID:18845535)
• 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)
• In conclusion, Multiplex Ligation-dependent Probe Amplification assessment of rearrangements in the RET proto-oncogene and in 3 other associated genes, ZEB2, EDN3 and GDNF did not show any variants in 80 sporadic Hirschsprung disease patients. (PMID:19183406)
• Common variants of the GDNF gene do not influence kidney size of the healthy newborn. (PMID:19184120)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gdnfa	ENSDARG00000039959
danio_rerio	gdnfb	ENSDARG00000103764
mus_musculus	Gdnf	ENSMUSG00000022144
rattus_norvegicus	Gdnf	ENSRNOG00000083179

Paralogs (3): ARTN (ENSG00000117407), PSPN (ENSG00000125650), NRTN (ENSG00000171119)

Protein

Protein identifiers

Glial cell line-derived neurotrophic factor — P39905 (reviewed: P39905)

Alternative names: Astrocyte-derived trophic factor

All UniProt accessions (4): P39905, A0A0C4DGC2, A0A0S2Z3T2, A0A0S2Z3V2

UniProt curated annotations — full annotation on UniProt →

Function. Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake. Acts by binding to its coreceptor, GFRA1, leading to autophosphorylation and activation of the RET receptor. Involved in the development of the neural crest.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with GFRA1 coreceptor and RET: forms a 2:2:2 ternary complex composed of GDNF ligand, GFRA1 and RET receptor. Interacts (via propeptide) with SORL1 (via N-terminal ectodomain); this interaction affects GDNF-regulated, but not constitutive secretion. Also interacts with SORL1 in complex with GFRA1; this interaction leads to GDNF endocytosis and lysosomal degradation.

Subcellular location. Secreted.

Tissue specificity. In the brain, predominantly expressed in the striatum with highest levels in the caudate and lowest in the putamen. Isoform 2 is absent from most tissues except for low levels in intestine and kidney. Highest expression of isoform 3 is found in pancreatic islets. Isoform 5 is expressed at very low levels in putamen, nucleus accumbens, prefrontal cortex, amygdala, hypothalamus and intestine. Isoform 3 is up-regulated in the middle temporal gyrus of Alzheimer disease patients while isoform 2 shows no change.

Disease relevance. Hirschsprung disease 3 (HSCR3) [MIM:613711] A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. Disease susceptibility is associated with variants affecting the gene represented in this entry. Pheochromocytoma (PCC) [MIM:171300] A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. The gene represented in this entry may act as a disease modifier.

Induction. By cAMP, 12-O-tetradecanoylphorbol-13-acetate (TPA) and FGF2.

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

Isoforms (5)

UniProt ID	Names	Canonical?
P39905-1	1, Ex1_4L	yes
P39905-2	2, ATF-1, Ex1_4S, Ex3_4S, GDNF delta 78, HFK2-GDNF
P39905-3	3, Ex2_4L, HFK3-GDNF
P39905-4	4, HFK4-GDNF
P39905-5	5, Ex4S_5

RefSeq proteins (5): NP_000505, NP_001177397, NP_001177398, NP_001265027, NP_954701 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001839	TGF-b_C	Domain
IPR016649	GDNF	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily
IPR043401	GDNF_fam	Family
IPR047020	GDNF_TGF-b-like	Domain

Pfam: PF00019

UniProt features (30 total): strand 7, sequence variant 5, disulfide bond 4, splice variant 3, helix 2, region of interest 2, glycosylation site 2, signal peptide 1, propeptide 1, chain 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2V5E	X-RAY DIFFRACTION	2.35
3FUB	X-RAY DIFFRACTION	2.35
6Q2N	ELECTRON MICROSCOPY	4.4
4UX8	ELECTRON MICROSCOPY	24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P39905-F1	75.29	0.36

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): 149–210, 178, 118–179, 145–208

Glycosylation sites (2): 126, 162

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-419037	NCAM1 interactions
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8853659	RET signaling
R-HSA-9830674	Formation of the ureteric bud

MSigDB gene sets: 668 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, FXR_IR1_Q6, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, AP1_01, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3

GO Biological Process (43): metanephros development (GO:0001656), branching involved in ureteric bud morphogenesis (GO:0001658), neural crest cell migration (GO:0001755), organ induction (GO:0001759), postsynaptic membrane organization (GO:0001941), mesenchymal to epithelial transition involved in metanephros morphogenesis (GO:0003337), signal transduction (GO:0007165), nervous system development (GO:0007399), peripheral nervous system development (GO:0007422), positive regulation of cell population proliferation (GO:0008284), adult locomotory behavior (GO:0008344), regulation of gene expression (GO:0010468), dorsal spinal cord development (GO:0021516), postganglionic parasympathetic fiber development (GO:0021784), peristalsis (GO:0030432), neuron projection development (GO:0031175), positive regulation of dopamine secretion (GO:0033603), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860), negative regulation of apoptotic process (GO:0043066), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of cell differentiation (GO:0045597), positive regulation of transcription by RNA polymerase II (GO:0045944), mRNA stabilization (GO:0048255), enteric nervous system development (GO:0048484), sympathetic nervous system development (GO:0048485), embryonic organ development (GO:0048568), regulation of dopamine uptake involved in synaptic transmission (GO:0051584), ureteric bud formation (GO:0060676), regulation of morphogenesis of a branching structure (GO:0060688), commissural neuron axon guidance (GO:0071679), positive regulation of ureteric bud formation (GO:0072107), positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis (GO:0072108), positive regulation of branching involved in ureteric bud morphogenesis (GO:0090190), neural crest cell migration involved in autonomic nervous system development (GO:1901166), regulation of stem cell differentiation (GO:2000736), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), regulation of semaphorin-plexin signaling pathway (GO:2001260), ureteric bud development (GO:0001657), tissue development (GO:0009888), neuron differentiation (GO:0030182)

GO Molecular Function (7): 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), protein homodimerization activity (GO:0042803), chemoattractant activity involved in axon guidance (GO:1902379), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
kidney development	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
neural crest cell development	1
mesenchymal cell migration	1
regulation of animal organ formation	1
specification of animal organ identity	1
developmental induction	1
positive regulation of animal organ morphogenesis	1
membrane organization	1
postsynapse organization	1
metanephros morphogenesis	1
epithelial cell differentiation involved in kidney development	1
mesenchymal to epithelial transition	1
metanephric renal vesicle morphogenesis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
nervous system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
locomotory behavior	1
adult behavior	1
gene expression	1
regulation of macromolecule biosynthetic process	1
spinal cord development	1
anatomical structure development	1
peripheral nervous system development	1
autonomic nervous system development	1
parasympathetic nervous system development	1
phasic smooth muscle contraction	1
neuron development	1
plasma membrane bounded cell projection organization	1
dopamine secretion	1
regulation of dopamine secretion	1
positive regulation of catecholamine secretion	1

Protein interactions and networks

STRING

2584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GDNF	GFRA1	P56159	999
GDNF	RET	P07949	999
GDNF	GFRA2	O00451	998
GDNF	NTRK2	Q16620	994
GDNF	NTRK1	P04629	991
GDNF	GFRA3	O60609	990
GDNF	GFRA4	Q9GZZ7	978
GDNF	JUN	P05412	975
GDNF	NTRK3	Q16288	972
GDNF	BDNF	P23560	963
GDNF	NTF3	P20783	936
GDNF	FOS	P01100	934
GDNF	NGF	P01138	925
GDNF	CNTF	P26441	913
GDNF	EDNRB	P24530	901

IntAct

10 interactions, top by confidence:

A	B	Type	Score
PTPRA	PTPRE	psi-mi:“MI:0914”(association)	0.640
AGTRAP	GDNF	psi-mi:“MI:0915”(physical association)	0.560
GDNF	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
GDNF	AGTRAP	psi-mi:“MI:0915”(physical association)	0.490
SORL1	GDNF	psi-mi:“MI:0407”(direct interaction)	0.440
NDUFS6	GDNF	psi-mi:“MI:0915”(physical association)	0.400
GDNF	RANBP10	psi-mi:“MI:0914”(association)	0.350

BioGRID (37): AGTRAP (Two-hybrid), MAEA (Affinity Capture-MS), MKLN1 (Affinity Capture-MS), RMND5A (Affinity Capture-MS), RANBP9 (Affinity Capture-MS), RANBP10 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), S100A10 (Affinity Capture-MS), GID4 (Affinity Capture-MS), YPEL5 (Affinity Capture-MS), AGTRAP (Two-hybrid), GID4 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), MAEA (Affinity Capture-MS), GDNF (Affinity Capture-MS)

ESM2 similar proteins: A0MTF4, M3X9S6, O35757, O35793, O54693, O60565, O70326, O73753, O73754, O73755, O88273, P09858, P12034, P15656, P20827, P21214, P27090, P30371, P39905, P41271, P48540, P48807, P49767, P50291, P61811, P61812, P97401, P97553, P97953, Q06880, Q06AS9, Q07257, Q07731, Q20FD0, Q38L25, Q61477, Q6DF53, Q6NW40, Q6NZ13, Q7TQ33

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

SIGNOR signaling

24 interactions.

A	Effect	B	Mechanism
GDNF	“up-regulates activity”	GCH1
GDNF	up-regulates	GFRA1	binding
GDNF	up-regulates	RET	binding
GDNF	up-regulates	GFRA2	binding
GDNF	up-regulates	Neural_tissue_regeneration
GDNF	“down-regulates quantity by repression”	PAFAH1B1	“transcriptional regulation”
GDNF	“down-regulates quantity by repression”	DCX	“transcriptional regulation”
GDNF	“down-regulates quantity by repression”	DNM2	“transcriptional regulation”
GDNF	“down-regulates quantity by repression”	TUBA1A	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	LAMA3	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	MAP1LC3B	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	ALCAM	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	BIN1	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	ID1	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	ID2	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	ID3	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	NRG1	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	NRN1	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	PTK2	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	RHOQ	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	PDPK1	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	CLU	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	FST	“transcriptional regulation”
GDNF	“up-regulates activity”	NCAM1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	122
Likely benign	21
Benign	28

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
154811	GRCh38/hg38 2q31.1(chr2:173713838-175467462)x1	Pathogenic
446338	GRCh37/hg19 2q31.1(chr2:175887486-176989647)x1	Pathogenic
562670	GRCh37/hg19 2q31.1(chr2:171667051-176832848)x3	Pathogenic
58768	GRCh38/hg38 2q31.1(chr2:173699279-175586070)x1	Pathogenic
253337	GRCh37/hg19 2q31.1(chr2:174586724-176423918)x1	Likely pathogenic

SpliceAI

4123 predictions. Top by Δscore:

Variant	Effect	Δscore
12:50770154:GTT:G	donor_gain	1.0000
12:50770157:G:GG	donor_gain	1.0000
12:50775659:G:GG	donor_gain	1.0000
12:50780135:TATA:T	acceptor_loss	1.0000
12:50780136:ATAG:A	acceptor_loss	1.0000
12:50780137:T:G	acceptor_gain	1.0000
12:50780137:TAGT:T	acceptor_loss	1.0000
12:50780138:A:AG	acceptor_gain	1.0000
12:50780138:AGTT:A	acceptor_gain	1.0000
12:50780139:G:GA	acceptor_gain	1.0000
12:50780139:GT:G	acceptor_gain	1.0000
12:50780139:GTT:G	acceptor_gain	1.0000
12:50780139:GTTG:G	acceptor_gain	1.0000
12:50780139:GTTGA:G	acceptor_gain	1.0000
12:50780209:G:GT	donor_gain	1.0000
12:50780234:AACAG:A	donor_loss	1.0000
12:50780239:G:GC	donor_loss	1.0000
12:50780240:T:A	donor_loss	1.0000
12:50795908:GGT:G	acceptor_gain	1.0000
12:50796007:CAG:C	donor_gain	1.0000
12:50796008:AG:A	donor_gain	1.0000
12:50796009:GG:G	donor_gain	1.0000
12:50796009:GGTG:G	donor_loss	1.0000
12:50796010:G:GG	donor_gain	1.0000
12:50809455:GAAAA:G	acceptor_gain	1.0000
12:50809585:GTACA:G	donor_gain	1.0000
12:50809588:CAGT:C	donor_loss	1.0000
12:50809589:AGTA:A	donor_loss	1.0000
12:50809590:G:GG	donor_gain	1.0000
12:50809591:T:G	donor_loss	1.0000

AlphaMissense

1377 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:37815718:A:C	F190C	1.000
5:37815718:A:G	F190S	1.000
5:37815745:G:T	P181H	1.000
5:37815852:G:C	C145W	1.000
5:37815663:A:C	C208W	0.999
5:37815664:C:G	C208S	0.999
5:37815665:A:G	C208R	0.999
5:37815665:A:T	C208S	0.999
5:37815673:G:T	A205D	0.999
5:37815677:A:G	S204P	0.999
5:37815697:T:C	Y197C	0.999
5:37815715:A:G	L191S	0.999
5:37815717:A:C	F190L	0.999
5:37815717:A:T	F190L	0.999
5:37815719:A:G	F190L	0.999
5:37815745:G:C	P181R	0.999
5:37815746:G:A	P181S	0.999
5:37815746:G:T	P181T	0.999
5:37815750:G:C	C179W	0.999
5:37815751:C:G	C179S	0.999
5:37815751:C:T	C179Y	0.999
5:37815752:A:G	C179R	0.999
5:37815752:A:T	C179S	0.999
5:37815841:C:T	C149Y	0.999
5:37815848:C:A	G147C	0.999
5:37815853:C:A	C145F	0.999
5:37815853:C:G	C145S	0.999
5:37815853:C:T	C145Y	0.999
5:37815854:A:G	C145R	0.999
5:37815854:A:T	C145S	0.999

dbSNP variants (sampled 300 via entrez): RS1000021131 (5:37815140 T>C), RS1000168867 (5:37839978 G>A,T), RS1000328687 (5:37820475 G>A,C), RS1000403828 (5:37833793 T>G), RS1000561580 (5:37823498 A>T), RS1000626559 (5:37816748 G>C), RS1000692685 (5:37815373 A>G), RS1000747647 (5:37815690 A>G), RS1000883626 (5:37841747 G>A), RS1000927371 (5:37821765 C>G), RS1001104774 (5:37828687 T>C), RS1001133545 (5:37823066 T>C,G), RS1001174109 (5:37829727 C>T), RS1001250542 (5:37815033 G>A,C), RS1001276201 (5:37821589 G>A)

Disease associations

OMIM: gene MIM:600837 | disease phenotypes: MIM:613711, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
Hirschsprung disease, susceptibility to, 3	Limited	Autosomal dominant

Mondo (3): Hirschsprung disease, susceptibility to, 3 (MONDO:0013383), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), Hirschsprung disease (MONDO:0018309)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001561	Polyhydramnios
HP:0001824	Weight loss
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002093	Respiratory insufficiency
HP:0002251	Aganglionic megacolon
HP:0002270	Abnormality of the autonomic nervous system
HP:0003005	Ganglioneuroma
HP:0003006	Neuroblastoma
HP:0003270	Abdominal distention
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0004387	Enterocolitis
HP:0005214	Intestinal obstruction
HP:0006747	Ganglioneuroblastoma
HP:0011285	Long-segment aganglionic megacolon
HP:0011286	Total colonic aganglionosis
HP:0011968	Feeding difficulties
HP:0012719	Functional abnormality of the gastrointestinal tract
HP:0031369	Colon perforation
HP:0034754	Bilious emesis
HP:0100006	Neoplasm of the central nervous system
HP:0100543	Cognitive impairment

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000578_7	Major depressive disorder	1.000000e-06
GCST005212_31	Asthma	3.000000e-06
GCST008759_40	Intake of total sugars	8.000000e-07
GCST009391_1749	Metabolite levels	6.000000e-07
GCST010396_232	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010158	sugar consumption measurement
EFO:0010349	cholesteryl ester 20:5 measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
C538121	Hirschsprung disease type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2216711	Efficacy	3	paroxetine	Major Depressive Disorder
rs2973049	Efficacy	3	paroxetine	Major Depressive Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2216711	GDNF	3	2.00	1	paroxetine
rs2973049	GDNF	3	2.75	1	paroxetine

CTD chemical–gene interactions

70 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
1-Methyl-4-phenylpyridinium	decreases expression, decreases reaction, affects cotreatment, increases response to substance	3
Cyclic AMP	increases expression, decreases response to substance, affects cotreatment, decreases reaction, increases response to substance (+1 more)	2
Cisplatin	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, decreases methylation	2
Tretinoin	affects expression, increases secretion, increases activity	2
Aflatoxin B1	increases expression	2
aminomethylphosphonic acid (AMPA)	increases expression	1
methylmercuric chloride	affects methylation, affects phosphorylation, affects binding, affects cotreatment, affects expression (+1 more)	1
methyleugenol	increases expression	1
bisphenol A	decreases methylation	1
titanium dioxide	decreases methylation, increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	increases methylation	1
potassium chromate(VI)	increases expression	1
nickel sulfate	decreases expression	1
rasagiline	increases expression, decreases reaction	1
puerarin	decreases expression, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	1
diallyl trisulfide	increases expression	1
vanoxerine	affects cotreatment, decreases reaction, increases response to substance	1
cordycepin	increases secretion	1
echinacoside	decreases expression, decreases reaction	1
chromium hexavalent ion	increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DF67	NGC-0301	Spontaneously immortalized cell line	Male
CVCL_DF68	NGC-0363	Spontaneously immortalized cell line	Male
CVCL_IQ62	ARPE-19/GDNF	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06197061	Not specified	UNKNOWN	Comparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)