GDNF

protein-coding

glial cell derived neurotrophic factor, the group of GDNF family ligands

Gene summary

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. [provided by RefSeq, Aug 2016]

MANE transcript

NM_000514.4

Inheritance

ClinVar variants

U:27B:15

Top phenotype

Central hypoventilation syndrome; Hirschsprung disease, susceptibility to, 3

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr5:37,812,677-37,840,041

External References & Databases

Ensembl (ENSG00000168621)

Transcript & Mutation Effects

hg38 • Region Span ~27.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hirschsprung disease, susceptibility to, 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013383

Submitter: PanelApp Australia

cystic kidney diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0002473

Submitter: PMGRC

Clinical Genomic Database (CGD)

Central hypoventilation syndrome; Hirschsprung disease, susceptibility to, 3AD

Manifestation: Gastrointestinal; Neurologic

Intervention: Gastrointestinal; Neurologic

Rationale: In Central hypoventilation syndrome, early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality; In conditions that may involve Hirschsprung disease, recognition of potential GI anomalies (eg, aganglionosis) may allow prompt recognition and treatment

Refs: 8896568; 8968758; 8896569; 9497256; 11973622; 11823451; 22729463

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GDNF variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 30

not providedTotal: 15

Hirschsprung disease, susceptibility to, 3Total: 15

GDNF-related disorderTotal: 9

Aganglionic megacolonTotal: 1

Hirschsprung disease, susceptibility to, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000514.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				8 clinvar		8
missense			27 clinvar	7 clinvar		34
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	27	15	0	42

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000514.4	RefSeq	NP_000505.1	2	MANE Select
ENST00000326524.7	Ensembl	ENSP00000317145.2	2	MANE Select
NM_001190468.1	RefSeq	NP_001177397.1	3	Standard
NM_001190469.1	RefSeq	NP_001177398.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gdnfa	Danio rerio	Structure: afferent neuron Quality: truncated abnormal

Gene / Model

Organism

Observed Phenotype

gdnfa

Danio rerio

Structure: afferent neuron

Quality: truncated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Allograft Rejection
Spinal Cord Injury
Developmental Biology
Signal Transduction
GPCR signaling-G alpha q

Biological Process

MAPK cascade
metanephros development
branching involved in ureteric bud morphogenesis
neural crest cell migration
organ induction

Molecular Function

Ras guanyl-nucleotide exchange factor activity
signaling receptor binding
protein binding
growth factor activity
protein homodimerization activity

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000427982
Coding exons: 3
Length: 27010
Individuals with no LoFs: 123085
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 123086
p: 0.00000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.10	100	136	0.735	0.00000741	1483
Missense (PolyPhen)		22	45.424	0.48432		544
Synonymous	-0.973	67	57.6	1.16	0.00000343	459
Loss of Function	1.72	2	6.86	0.292	2.89e-7	97

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake. {ECO:0000269|PubMed:8493557}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:10917288, ECO:0000269|PubMed:8896568, ECO:0000269|PubMed:8896569, ECO:0000269|PubMed:8968758}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Congenital central hypoventilation syndrome (CCHS) [MIM:209880]: 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. {ECO:0000269|PubMed:9497256}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:9215674}. Note=The gene represented in this entry may act as a disease modifier.;

Recessive Scores

pRec: 0.714

Intolerance Scores

LoFtool: 0.0280
RVIS EVS: 0.19
RVIS percentile EVS: 66.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.673

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium