[1]	NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, HOMODIMERIZATION, AND DISULFIDE BONDS. PubMed=8493557 [NCBI, ExPASy, EBI, Israel, Japan] Lin L.-F.H., Doherty D.H., Lile J.D., Bektesh S., Collins F.; "GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons."; Science 260:1130-1132(1993).
[2]	NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY. DOI=10.1006/exnr.1994.1218; PubMed=7867768 [NCBI, ExPASy, EBI, Israel, Japan] Schaar D.G., Sieber B.-A., Sherwood A.C., Dean D., Mendoza G., Ramakrishnan L., Dreyfus C.F., Black I.B.; "Multiple astrocyte transcripts encode nigral trophic factors in rat and human."; Exp. Neurol. 130:387-393(1994).
[3]	NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Zhang B., Feng Z., Zhou Y., Peng X., Yuan J., Qiang B.; Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases.
[4]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; "Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."; Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
[5]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan] The MGC Project Team; "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."; Genome Res. 14:2121-2127(2004).
[6]	NUCLEOTIDE SEQUENCE [MRNA] OF 1-187 (ISOFORM 1). TISSUE=Fetal kidney; DOI=10.1016/S0169-328X(99)00106-0; PubMed=10366742 [NCBI, ExPASy, EBI, Israel, Japan] Baecker P.A., Lee W.H., Verity A.N., Eglen R.M., Johnson R.M.; "Characterization of a promoter for the human glial cell line-derived neurotrophic factor gene."; Brain Res. Mol. Brain Res. 69:209-222(1999).
[7]	NUCLEOTIDE SEQUENCE [MRNA] OF 1-88 (ISOFORM 2), NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-77, AND NUCLEOTIDE SEQUENCE [MRNA] OF 1-59 (ISOFORMS 3 AND 4). TISSUE=Brain, and Kidney; Suter-Crazzolara C., Baecker P.A., Lee W.H., Johnson R.M., Unsicker K.; "The Human GDNF Gene promoter."; Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases.
[8]	NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50, SUBCELLULAR LOCATION, AND INDUCTION. DOI=10.1093/hmg/7.12.1873; PubMed=9811930 [NCBI, ExPASy, EBI, Israel, Japan] Grimm L., Holinski-Feder E., Teodoridis J., Scheffer B., Schindelhauer D., Meitinger T., Ueffing M.; "Analysis of the human GDNF gene reveals an inducible promoter, three exons, a triplet repeat within the 3'-UTR and alternative splice products."; Hum. Mol. Genet. 7:1873-1886(1998).
[9]	PROTEIN SEQUENCE OF 87-122; 141-153; 173-184 AND 196-211, HOMODIMERIZATION, AND DISULFIDE BONDS. DOI=10.1021/bi9605550; PubMed=8988018 [NCBI, ExPASy, EBI, Israel, Japan] Haniu M., Hui J., Young Y., Le J., Katta V., Lee R., Shimamoto G., Rohde M.F.; "Glial cell line-derived neurotrophic factor: selective reduction of the intermolecular disulfide linkage and characterization of its disulfide structure."; Biochemistry 35:16799-16805(1996).
[10]	REVIEW ON VARIANTS. PubMed=9359036 [NCBI, ExPASy, EBI, Israel, Japan] Hofstra R.M.W., Osinga J., Buys C.H.C.M.; "Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype."; Eur. J. Hum. Genet. 5:180-185(1997).
[11]	VARIANT HSCR SER-154. DOI=10.1093/hmg/5.12.2023; PubMed=8968758 [NCBI, ExPASy, EBI, Israel, Japan] Ivanchuk S.M., Myers S.M., Eng C., Mulligan L.M.; "De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease."; Hum. Mol. Genet. 5:2023-2026(1996).
[12]	VARIANT HSCR TRP-93. DOI=10.1038/ng1196-341; PubMed=8896568 [NCBI, ExPASy, EBI, Israel, Japan] Angrist M., Bolk S., Halushka M., Lapchak P.A., Chakravarti A.; "Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient."; Nat. Genet. 14:341-344(1996).
[13]	VARIANTS HSCR SER-21 AND ASN-150. DOI=10.1038/ng1196-345; PubMed=8896569 [NCBI, ExPASy, EBI, Israel, Japan] Salomon R., Attie T., Pelet A., Bidaud C., Eng C., Amiel J., Sarnacki S., Goulet O., Ricour C., Nihoul-Fekete C., Munnich A., Lyonnet S.; "Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease."; Nat. Genet. 14:345-347(1996).
[14]	VARIANT CCHS TRP-93. DOI=10.1086/301759; PubMed=9497256 [NCBI, ExPASy, EBI, Israel, Japan] Amiel J., Salomon R., Attie T., Pelet A., Trang H., Mokhtari M., Gaultier C., Munnich A., Lyonnet S.; "Mutations of the RET-GDNF signaling pathway in Ondine's curse."; Am. J. Hum. Genet. 62:715-717(1998).
[15]	VARIANT HSCR MET-211. DOI=10.1053/jpsu.2000.7763; PubMed=10917288 [NCBI, ExPASy, EBI, Israel, Japan] Martucciello G., Ceccherini I., Lerone M., Jasonni V.; "Pathogenesis of Hirschsprung's disease."; J. Pediatr. Surg. 35:1017-1025(2000).

Comments

FUNCTION: Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.
SUBUNIT: Homodimer; disulfide-linked.
SUBCELLULAR LOCATION: Secreted.

ALTERNATIVE PRODUCTS: 4 named isoforms [FASTA] produced by alternative splicing.

Name	1
Isoform ID	P39905-1
This is the isoform sequence displayed in this entry.

Name	2
Synonyms	ATF-1, HFK2-GDNF
Isoform ID	P39905-2
Features which should be applied to build the isoform sequence: VSP_006420.

Name	3
Synonyms	HFK3-GDNF
Isoform ID	P39905-3
Features which should be applied to build the isoform sequence: VSP_026368.

Name	4
Synonyms	HFK4-GDNF
Isoform ID	P39905-4
Features which should be applied to build the isoform sequence: VSP_026368, VSP_006420.

TISSUE SPECIFICITY: In the brain, predominantly expressed in the striatum with highest levels in the caudate and lowest in the putamen.
INDUCTION: By cAMP, tetradecanoyl 12-phorbol acetate and fibroblast growth factor 2.
DISEASE: Defects in GDNF may be a cause of Hirschsprung disease (HSCR) [MIM:142623]. In association with mutations of RET gene, defects in GDNF may be involved in Hirschsprung disease. This genetic disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.
DISEASE: Defects in GDNF are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:209880]; also known as congenital failure of autonomic control or Ondine curse. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia.
SIMILARITY: Belongs to the TGF-beta family. GDNF subfamily.
WEB RESOURCE: Name=R&D Systems' cytokine mini-reviews: GDNF; URL="http://www.rndsystems.com/molecule_detail.aspx?m=1510";.
WEB RESOURCE: Name=GeneReviews; URL="http://www.genetests.org/query?gene=GDNF";.

Copyright

Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.

Cross-references

Sequence databases

EMBL

L19063; AAA67910.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
L19062; AAA67910.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AY052832; AAL11017.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
CR541923; CAG46721.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC069119; AAH69119.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC069369; AAH69369.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC128108; AAI28109.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC128109; AAI28110.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF053748; AAD43139.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ001896; CAA05074.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ001897; CAA05075.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ001898; CAA05076.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ001899; CAA05077.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ001900; CAA05078.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF063586; AAC98782.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]

PIR

B37499; B37499.

RefSeq

NP_000505.1; -.
NP_954701.1; -.
NP_954704.1; -.

UniGene

Hs.248114

3D structure databases

HSSP

Q07731; 1AGQ. [HSSP ENTRY / PDB]

SMR

P39905; 117-211.

ModBase

P39905.

Organism-specific databases

HIX0031958; -.

HGNC:4232; GDNF.

CAB005210; -.

142623; phenotype. [NCBI / EBI]
209880; phenotype. [NCBI / EBI]
600837; gene. [NCBI / EBI]

Orphanet

388; Hirschsprung disease.
661; Ondine syndrome.

PharmGKB

PA28644; -.

GeneCards

P39905.

Gene expression databases

ArrayExpress

P39905; -.

GermOnline

ENSG00000168621; Homo sapiens.

Ontologies

GO:0005576;	Cellular component: extracellular region (inferred from direct assay from UniProtKB).
GO:0008083;	Molecular function: growth factor activity (non-traceable author statement from UniProtKB).
GO:0042803;	Molecular function: protein homodimerization activity (inferred from direct assay from UniProtKB).
GO:0006916;	Biological process: anti-apoptosis (traceable author statement from ProtInc).
GO:0043524;	Biological process: negative regulation of neuron apoptosis (inferred from direct assay from UniProtKB).
GO:0001755;	Biological process: neural crest cell migration (inferred from direct assay from MGI).
GO:0031175;	Biological process: neurite development (inferred from direct assay from MGI).
GO:0051584;	Biological process: regulation of dopamine uptake (inferred from direct assay from UniProtKB).
GO:0007165;	Biological process: signal transduction (traceable author statement from ProtInc).
QuickGo view.

Family and domain databases

InterPro

IPR016649; GDNF.
IPR002400; GF_cysknot.
IPR001839; TGFb.
Graphical view of domain structure.

Pfam

PF00019; TGF_beta; 1.
Pfam graphical view of domain structure.

PIRSF

PIRSF016238; GDNF; 1.

PRINTS

PR00438; GFCYSKNOT.

ProDom

PD000357; TGFb; 1.
[Domain structure / List of seq. sharing at least 1 domain]

SMART

SM00204; TGFB; 1.
SMART graphical view of domain structure.

PROSITE

PS00250; TGF_BETA_1; FALSE_NEG.
PS51362; TGF_BETA_2; 1.
PROSITE graphical view of domain structure (profiles).

BLOCKS

P39905.

Genome annotation databases

Ensembl

ENSG00000168621; Homo sapiens. [Contig view]

GeneID

2668; -.

KEGG

hsa:2668; -.

Phylogenomic databases

HOGENOM

P39905; -.

HOVERGEN

P39905; -.

Other

GDNF; Homo sapiens.

View cluster of proteins with at least 50% / 90% / 100% identity.

Keywords

Alternative splicing; Cleavage on pair of basic residues; Direct protein sequencing; Disease mutation; Glycoprotein; Growth factor; Hirschsprung disease; Polymorphism; Secreted; Signal.

Features

Feature table viewer

Feature aligner

`Key`	`From To`	`Length`	`Description`	`FTId`
`SIGNAL`	`1 19`	`19`	`Potential.`
`PROPEP`	`20 75`	`56`	`By similarity.`	`PRO_0000034004`
`CHAIN`	`78 211`	`134`	`Glial cell line-derived neurotrophic factor.`	`PRO_0000034005`
`CARBOHYD`	`126 126`		`N-linked (GlcNAc...) (Potential).`
`CARBOHYD`	`162 162`		`N-linked (GlcNAc...) (Potential).`
`DISULFID`	`118 179`
`DISULFID`	`145 208`
`DISULFID`	`149 210`
`DISULFID`	`178 178`		`Interchain.`
`VAR_SEQ`	`1 1`		`M -> MQSLPNSNGAAAGRDFKM (in isoform 3 and isoform 4).`	`VSP_026368`
`VAR_SEQ`	`25 51`		`GKRPPEAPAEDRSLGRRRAPFALSSDS -> A (in isoform 2 and isoform 4).`	`VSP_006420`
`VARIANT`	`21 21`	`1`	`P -> S (in HSCR; could be a polymorphism).`	`VAR_009494`
`VARIANT`	`93 93`	`1`	`R -> W (in HSCR and CCHS; associated to a RET mutation; could be an extremely rare polymorphism).`	`VAR_009495`
`VARIANT`	`150 150`	`1`	`D -> N (in HSCR; could be a polymorphism).`	`VAR_009496 [3D]`
`VARIANT`	`154 154`	`1`	`T -> S (in HSCR; sporadic form).`	`VAR_009497 [3D]`
`VARIANT`	`211 211`	`1`	`I -> M (in HSCR).`	`VAR_018152 [3D]`

Sequence information

Length: 211 AA [This is the length of the unprocessed precursor]

Molecular weight: 23720 Da [This is the MW of the unprocessed precursor]

CRC64: A0D1EBF77FC82691 [This is a checksum on the sequence]

        10         20         30         40         50         60 
MKLWDVVAVC LVLLHTASAF PLPAGKRPPE APAEDRSLGR RRAPFALSSD SNMPEDYPDQ 

        70         80         90        100        110        120 
FDDVMDFIQA TIKRLKRSPD KQMAVLPRRE RNRQAAAANP ENSRGKGRRG QRGKNRGCVL 

       130        140        150        160        170        180 
TAIHLNVTDL GLGYETKEEL IFRYCSGSCD AAETTYDKIL KNLSRNRRLV SDKVGQACCR 

       190        200        210 
PIAFDDDLSF LDDNLVYHIL RKHSAKRCGC I

P39905 in FASTA format

View entry in original UniProtKB/Swiss-Prot format
View entry in raw text format (no links)
Report form for errors/updates in this UniProtKB/Swiss-Prot entry

	BLAST submission on ExPASy/SIB or at NCBI (USA)		Sequence analysis tools: ProtParam, ProtScale, Compute pI/Mw, PeptideMass, PeptideCutter, Dotlet (Java)
	ScanProsite, MotifScan		Submit a homology modeling request to SWISS-MODEL
	NPSA Sequence analysis tools