NRTN

Summary

NRTN (neurturin, HGNC:8007) is a protein-coding gene on chromosome 19p13.3, encoding Neurturin (Q99748). Growth factor that supports the survival of sympathetic neurons in culture.

This gene encodes a secreted ligand of the 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. A neurturin mutation has been described in a family with Hirschsprung Disease.

Source: NCBI Gene 4902 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 57 total
• Phenotypes (HPO): 19
• MANE Select transcript: NM_004558

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8007
Approved symbol	NRTN
Name	neurturin
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	NTN
Ensembl gene	ENSG00000171119
Ensembl biotype	protein_coding
OMIM	602018
Entrez	4902

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000303212, ENST00000879152, ENST00000936080, ENST00000936081, ENST00000953122, ENST00000953123

RefSeq mRNA: 1 — MANE Select: NM_004558 NM_004558

CCDS: CCDS12151

Canonical transcript exons

ENST00000303212 — 3 exons

Exon	Start	End
ENSE00001158050	5827749	5828324
ENSE00001204668	5823768	5824334
ENSE00003922361	5805067	5805451

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 89.52.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8842 / max 24.7788, expressed in 370 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173434	0.8842	370

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	89.52	gold quality
right atrium auricular region	UBERON:0006631	89.00	gold quality
cardiac atrium	UBERON:0002081	88.38	gold quality
heart left ventricle	UBERON:0002084	82.56	gold quality
body of pancreas	UBERON:0001150	81.90	gold quality
cardiac ventricle	UBERON:0002082	81.77	gold quality
lower esophagus	UBERON:0013473	81.35	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.35	gold quality
lower esophagus mucosa	UBERON:0035834	80.48	gold quality
right lobe of liver	UBERON:0001114	79.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.01	silver quality
body of stomach	UBERON:0001161	78.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	78.53	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.26	gold quality
heart	UBERON:0000948	77.48	gold quality
amniotic fluid	UBERON:0000173	77.42	silver quality
left adrenal gland cortex	UBERON:0035825	77.02	gold quality
esophagus	UBERON:0001043	76.38	gold quality
left adrenal gland	UBERON:0001234	75.68	gold quality
right adrenal gland cortex	UBERON:0035827	75.28	gold quality
adrenal cortex	UBERON:0001235	74.56	gold quality
right adrenal gland	UBERON:0001233	74.39	gold quality
stomach	UBERON:0000945	74.03	gold quality
esophagus mucosa	UBERON:0002469	72.79	gold quality
skin of leg	UBERON:0001511	72.69	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	72.56	gold quality
liver	UBERON:0002107	71.94	gold quality
adrenal gland	UBERON:0002369	71.53	gold quality
sigmoid colon	UBERON:0001159	71.46	gold quality
minor salivary gland	UBERON:0001830	71.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting NRTN, 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-3064-3P	100.00	70.09	1254
HSA-MIR-216B-3P	98.55	67.19	1223
HSA-MIR-4797-3P	97.48	67.14	989

Literature-anchored findings (GeneRIF, showing 16)

• GDNF and NRTN are new neuromodulators that regulate the development of the neuromuscular synapse (PMID:11790765)
• The gene expression of protein was studied in the developing human tooth. (PMID:12397373)
• 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)
• Addition of neurturin to activated peripheral blood mononuclear leukocytes reduces the amount of detectable tumor necrosis factor protein without altering its transcription. (PMID:16081799)
• GDNF and NTN differentially regulate the expression of distinct miRNA precursors through the activation of mitogen-activated protein kinase (PMID:16895582)
• Depending on the brain’s expressions of specific GDNF family GFRalpha2 receptor spliced isoforms, neurturin may promote or inhibit neurite outgrowth through the multicomponent receptor complex. (PMID:17522305)
• 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)
• 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)
• Cyclic AMP signalling through PKA but not Epac is essential for neurturin-induced biphasic ERK1/2 activation and neurite outgrowths through GFRalpha2 isoforms. (PMID:21723942)
• Human neurturin protected crayfish neurons and glia from photodynamic injury. (PMID:22847529)
• Neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer. (PMID:24067900)
• In the cochlea, NTN immunostaining was found in the supporting cells of organ of Corti, including Deiters’ cells, Hensen cells as well as Claudius’ cells. In the spiral ganglia, NTN was seen in both the cell bodies and the nerve fibers of neurons. (PMID:24139947)
• biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects. (PMID:29414779)
• We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRalpha2 and determined its structure at 5.7-A resolution by cryo-EM. The proteins form an assembly through RET-GFRalpha2 and RET-NRTN interfaces. (PMID:31392261)
• Refolding and purification of cGMP-grade recombinant human neurturin from Escherichia coli inclusion bodies. (PMID:31866372)
• TANGO1 interacts with NRTN to promote hepatocellular carcinoma progression by regulating the PI3K/AKT/mTOR signaling pathway. (PMID:37211171)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nrtn	ENSDARG00000079849
danio_rerio		ENSDARG00000110877
mus_musculus	Nrtn	ENSMUSG00000039481
rattus_norvegicus	Nrtn	ENSRNOG00000048651

Paralogs (3): ARTN (ENSG00000117407), PSPN (ENSG00000125650), GDNF (ENSG00000168621)

Protein

Protein identifiers

Neurturin — Q99748 (reviewed: Q99748)

All UniProt accessions (1): Q99748

UniProt curated annotations — full annotation on UniProt →

Function. Growth factor that supports the survival of sympathetic neurons in culture. May regulate the development and maintenance of the CNS. Involved in the development of the neural crest. Might control the size of non-neuronal cell population such as haemopoietic cells. Acts by binding to its coreceptor, GFRA2, leading to autophosphorylation and activation of the RET receptor. Heparan sulfate-binding is required for signaling.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with GFRA2 coreceptor and RET: forms a 2:2:2 ternary complex composed of NRTN ligand, GFRA2 and RET receptor. Also forms a 4:4:4 tetrameric complex composed of 4 copies of NRTN ligand, GFRA2 and RET receptor, which prevents endocytosis of RET.

Subcellular location. Secreted.

Disease relevance. Genetic variations in NRTN may contribute to Hirschsprung disease, in association with mutations of RET gene, and possibly mutations in other loci. Hirschsprung disease is a disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.

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

RefSeq proteins (1): NP_004549* (*=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 (24 total): strand 7, disulfide bond 4, binding site 4, helix 2, signal peptide 1, propeptide 1, sequence variant 1, mutagenesis site 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5NMZ	X-RAY DIFFRACTION	1.6
5MR5	X-RAY DIFFRACTION	2
5MR4	X-RAY DIFFRACTION	2.4
5MR9	X-RAY DIFFRACTION	2.4
6Q2O	ELECTRON MICROSCOPY	3.65
6Q2R	ELECTRON MICROSCOPY	4.3
6GL7	ELECTRON MICROSCOPY	6.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99748-F1	79.17	0.48

Functional residue map

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

Ligand- & substrate-binding residues (4): 149; 158; 160; 162

Disulfide bonds (4): 130–194, 134–196, 164, 103–165

Mutagenesis-validated functional residues (1):

Position	Phenotype
158–162	strongly decreased binding to heparan sulfate.

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: 192 (showing top): MORF_MSH3, MORF_BRCA1, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, MORF_ATRX, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, MORF_ESR1, MORF_RAD51L3, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, GOBP_NERVE_DEVELOPMENT, MORF_RAP1A, GOMF_GLYCOSAMINOGLYCAN_BINDING, MORF_ETV3

GO Biological Process (8): MAPK cascade (GO:0000165), neural crest cell migration (GO:0001755), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), nervous system development (GO:0007399), nerve development (GO:0021675), neuron projection development (GO:0031175), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860), cell surface receptor signaling pathway via STAT (GO:0097696)

GO Molecular Function (5): 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), heparan sulfate binding (GO:1904399)

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
intracellular signaling cassette	1
neural crest cell development	1
mesenchymal cell migration	1
enzyme-linked receptor protein signaling pathway	1
system development	1
nervous system development	1
anatomical structure development	1
neuron development	1
plasma membrane bounded cell projection organization	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cell surface receptor signaling pathway	1
protein binding	1
receptor ligand activity	1
growth factor receptor binding	1
signaling receptor binding	1
protein tyrosine kinase binding	1
glycosaminoglycan binding	1
carboxylic acid binding	1
sulfur compound binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NRTN	GFRA2	O00451	999
NRTN	GFRA1	P56159	999
NRTN	GFRA3	O60609	998
NRTN	RET	P07949	997
NRTN	GFRA4	Q9GZZ7	989
NRTN	NTRK1	P04629	859
NRTN	SDC3	O75056	824
NRTN	NTRK2	Q16620	792
NRTN	NGF	P01138	765
NRTN	BDNF	P23560	762
NRTN	NTRK3	Q16288	762
NRTN	GDNF	P39905	721
NRTN	CDNF	Q49AH0	720
NRTN	ARTN	Q5T4W7	715
NRTN	PSPN	O60542	704

IntAct

0 interactions, top by confidence:

BioGRID (5): NRTN (Reconstituted Complex), NRTN (Reconstituted Complex), NRTN (Affinity Capture-Western), NRTN (Reconstituted Complex), NRTN (Reconstituted Complex)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A8I5KY20, A2A9Q0, A9JSM3, B7Z1M9, B7ZBB8, B8ZZ34, C9JI98, D4A2Q0, E7ERA6, E9Q0B3, F1SAM7, F2Z333, F5H4A9, J3QNX5, O94819, P0C7L8, P0CG09, P0CG25, Q0IIA6, Q0PHV7, Q1RMK9, Q2M3D2, Q2M3V2, Q2MJR0, Q3ZCQ3, Q49LS1, Q5GH56, Q5GH64, Q5GH72, Q69YZ2, Q6NY19, Q6P6N5, Q6UKI2, Q6ZW31, Q7Z6J2, Q7Z736, Q86UD0, Q8BRJ4

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

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NRTN	up-regulates	GFRA1	binding
NRTN	up-regulates	RET	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	42
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

218 predictions. Top by Δscore:

Variant	Effect	Δscore
19:5824333:GT:G	donor_gain	1.0000
19:5824335:G:GG	donor_gain	1.0000
19:5823929:G:GT	donor_gain	0.9900
19:5824331:CAGT:C	donor_gain	0.9900
19:5827746:CAGAC:C	acceptor_loss	0.9900
19:5827747:A:AC	acceptor_loss	0.9900
19:5827747:A:AG	acceptor_gain	0.9900
19:5827748:G:GT	acceptor_gain	0.9900
19:5827748:GACC:G	acceptor_gain	0.9900
19:5823930:A:T	donor_gain	0.9800
19:5824330:CCAGT:C	donor_gain	0.9800
19:5824335:G:T	donor_loss	0.9800
19:5824336:T:TC	donor_loss	0.9800
19:5827747:AGACC:A	acceptor_gain	0.9800
19:5827748:GA:G	acceptor_gain	0.9800
19:5827748:GAC:G	acceptor_gain	0.9800
19:5827748:GACCG:G	acceptor_gain	0.9800
19:5827744:C:A	acceptor_gain	0.9600
19:5827746:CAGA:C	acceptor_gain	0.9600
19:5827747:AG:A	acceptor_gain	0.9500
19:5824359:C:A	donor_gain	0.9400
19:5827744:CGCA:C	acceptor_gain	0.9400
19:5827745:GCAG:G	acceptor_gain	0.9400
19:5827748:G:A	acceptor_gain	0.9300
19:5824332:AGT:A	donor_gain	0.9100
19:5824333:GTG:G	donor_gain	0.9100
19:5824334:TGT:T	donor_gain	0.9100
19:5824381:T:TA	donor_gain	0.9100
19:5824382:A:AA	donor_gain	0.9100
19:5824373:G:GG	donor_gain	0.9000

AlphaMissense

1204 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:5827959:T:G	F127C	0.999
19:5828105:T:C	F176L	0.999
19:5828106:T:G	F176C	0.999
19:5828107:C:A	F176L	0.999
19:5828107:C:G	F176L	0.999
19:5827959:T:C	F127S	0.998
19:5828106:T:C	F176S	0.998
19:5827941:C:T	S121F	0.997
19:5828079:C:A	P167Q	0.997
19:5827969:C:G	C130W	0.996
19:5827973:G:T	G132C	0.996
19:5828078:C:A	P167T	0.996
19:5828078:C:T	P167S	0.996
19:5827941:C:A	S121Y	0.995
19:5827968:G:A	C130Y	0.995
19:5827964:T:G	Y129D	0.994
19:5828127:A:G	Y183C	0.994
19:5827947:A:T	E123V	0.993
19:5828072:T:A	C165S	0.993
19:5828073:G:C	C165S	0.993
19:5827965:A:G	Y129C	0.992
19:5827967:T:A	C130S	0.992
19:5827968:G:C	C130S	0.992
19:5827980:G:A	C134Y	0.992
19:5828073:G:A	C165Y	0.992
19:5827968:G:T	C130F	0.991
19:5828079:C:G	P167R	0.991
19:5828079:C:T	P167L	0.991
19:5828112:A:T	D178V	0.990
19:5828159:T:A	C194S	0.990

dbSNP variants (sampled 300 via entrez): RS1000063449 (19:5821012 C>T), RS1000204663 (19:5805477 T>TG), RS1000538989 (19:5804136 C>A), RS1000766473 (19:5828686 C>T), RS1000849993 (19:5813358 A>G), RS1001037993 (19:5810112 A>G), RS1001065452 (19:5815274 T>C), RS1001181024 (19:5806921 G>A,C), RS1001199685 (19:5807291 C>T), RS1001206585 (19:5812426 T>C), RS1001251973 (19:5806821 C>T), RS1001252512 (19:5812492 C>A), RS1001371580 (19:5808538 C>G), RS1001702038 (19:5812123 G>A), RS1002007905 (19:5823059 GGAAA>G)

Disease associations

OMIM: gene MIM:602018 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
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:0002251	Aganglionic megacolon
HP:0003270	Abdominal distention
HP:0004322	Short stature
HP:0004387	Enterocolitis
HP:0005214	Intestinal obstruction
HP:0011968	Feeding difficulties
HP:0012719	Functional abnormality of the gastrointestinal tract
HP:0031369	Colon perforation
HP:0034754	Bilious emesis
HP:0100806	Sepsis
HP:6000224	Delayed passage of meconium

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000925_3	N-glycan levels	4.000000e-17
GCST000925_4	N-glycan levels	9.000000e-10
GCST000925_5	N-glycan levels	1.000000e-12
GCST000925_7	N-glycan levels	3.000000e-12
GCST003219_40	Advanced age-related macular degeneration	2.000000e-15
GCST005046_10	N-glycan levels	3.000000e-29
GCST005046_11	N-glycan levels	5.000000e-19
GCST005046_12	N-glycan levels	3.000000e-20
GCST005046_27	N-glycan levels	1.000000e-08
GCST005046_28	N-glycan levels	8.000000e-10
GCST005046_29	N-glycan levels	1.000000e-16
GCST005046_30	N-glycan levels	2.000000e-13
GCST005046_31	N-glycan levels	2.000000e-09
GCST005046_37	N-glycan levels	4.000000e-09
GCST005046_38	N-glycan levels	4.000000e-13
GCST005046_39	N-glycan levels	3.000000e-14
GCST005046_40	N-glycan levels	3.000000e-12
GCST005046_8	N-glycan levels	9.000000e-17
GCST005046_9	N-glycan levels	1.000000e-21
GCST007576_30	Chronotype	7.000000e-12
GCST008108_7	N-glycan levels	2.000000e-55

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004999	N-glycan measurement
EFO:1001492	atrophic macular degeneration
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, increases expression	4
bisphenol A	decreases expression, increases expression	3
trichostatin A	decreases expression, affects cotreatment	3
Aflatoxin B1	affects expression, decreases expression	3
methylmercuric chloride	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Estradiol	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Genistein	increases expression	2
bisphenol F	increases expression	1
fluorene-9-bisphenol	decreases expression	1
dicrotophos	decreases expression	1
triacsin C	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Decitabine	decreases expression, affects reaction	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	affects expression	1
Carmustine	decreases expression	1
Diethylstilbestrol	increases expression	1
Ethinyl Estradiol	increases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Urethane	increases expression	1

Clinical trials (associated diseases)

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