GFRA2 GDNF family receptor alpha 2 [Homo sapiens (human)] - Gene

Summary

Official Symbol: GFRA2provided by HGNC
Official Full Name: GDNF family receptor alpha 2provided by HGNC
Primary source: HGNC:HGNC:4244
See related: Ensembl:ENSG00000168546 MIM:601956; AllianceGenome:HGNC:4244
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: NTNRA; RETL2; TRNR2; GDNFRB; NRTNR-ALPHA
Summary: Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This encoded protein acts preferentially as a receptor for NTN compared to its other family member, GDNF family receptor alpha 1. This gene is a candidate gene for RET-associated diseases. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
Expression: Broad expression in spleen (RPKM 6.1), thyroid (RPKM 5.3) and 19 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 8p21.3

Exon count:: 13

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	8	NC_000008.11 (21690398..21812345, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	8	NC_060932.1 (21961568..22086203, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	8	NC_000008.10 (21547910..21646387, complement)

Chromosome 8 - NC_000008.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
Title: Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain.
GFRA2 was upregulated in human neuroblastoma cells and tissues, and promoted neuroblastoma cell proliferation through interacting with the tumor suppressor PTEN.
Title: GDNF family receptor alpha 2 promotes neuroblastoma cell proliferation by interacting with PTEN.
A novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 was identified to be associated with disease risk, and expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in GFRA2 tissue.
Title: Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.
biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects.
Title: Structure and biophysical characterization of the human full-length neurturin-GFRa2 complex: A role for heparan sulfate in signaling.
The cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase.
Title: GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.
High GFRalpha2 expression level leads to PTEN inactivation via Mir-17-5p up-regulation, promoting pancreatic tumor cell growth and chemoresistance.
Title: GFRα2 prompts cell growth and chemoresistance through down-regulating tumor suppressor gene PTEN via Mir-17-5p in pancreatic cancer.
GFRA2 variants associated with diabetic neuropathic pain.
Title: A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.
GFRalpha2 is under-expressed in functioning adenomas and over-expressed in non-functioning adenomas, specifically gonadotropinomas
Title: Expression of the pituitary stem/progenitor marker GFRα2 in human pituitary adenomas and normal pituitary.
In the cochlea, immunolabeling for GFRalpha-2 receptors was identified mainly in the cell bodies of the spiral neurons than in the nerve fibers. No structures in the organ of Corti were labeled with GFRalpha-2 receptor antibody
Title: Immunohistological analysis of neurturin and its receptors in human cochlea.
The study shows co-localization of RET with GFRA1 and GFRA2 in myenteric ganglia of the adult human colon.
Title: Site-specific gene expression and localization of growth factor ligand receptors RET, GFRα1 and GFRα2 in human adult colon.

Submit: New GeneRIF Correction See all GeneRIFs (20)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide meta-analysis identifies new susceptibility loci for migraine. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D8S1417E (e-PCR)
- UniSTS:44558

SHGC-31819 (e-PCR)
- UniSTS:24847

A003B30 (e-PCR)
- UniSTS:31517

WI-19670 (e-PCR)
- UniSTS:49240

D8S560 (e-PCR), detects polymorphism
- UniSTS:52858

SHGC-155724 (e-PCR)
- UniSTS:184803

SHGC-155725 (e-PCR)
- UniSTS:184804

D8S560 (e-PCR), detects polymorphism
- UniSTS:11253

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables glial cell-derived neurotrophic factor receptor activity	IBA Inferred from Biological aspect of Ancestor more info
enables glial cell-derived neurotrophic factor receptor activity	IDA Inferred from Direct Assay more info	PubMed
enables heparan sulfate binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in cell surface receptor protein tyrosine kinase signaling pathway	TAS Traceable Author Statement more info	PubMed
involved_in glial cell-derived neurotrophic factor receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in nervous system development	IBA Inferred from Biological aspect of Ancestor more info

Component	Evidence Code	Pubs
is_active_in external side of plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in extrinsic component of membrane	TAS Traceable Author Statement more info	PubMed
is_active_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info
part_of receptor complex	IBA Inferred from Biological aspect of Ancestor more info

General protein information

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Preferred Names: GDNF family receptor alpha-2

Names: GDNF receptor beta; GDNFR-alpha-2; GDNFR-beta; GFR-alpha 2; NTNR-alpha; PI-linked cell-surface accessory protein; RET ligand 2; TGF-beta-related neurotrophic factor receptor 2; TRN receptor, GPI-anchored; glial cell line derived neurotrophic factor receptor, beta; neurturin receptor alpha

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_029215.3 RefSeqGene

Range

28470..126947

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001165038.2 → NP_001158510.1 GDNF family receptor alpha-2 isoform b

See identical proteins and their annotated locations for NP_001158510.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an alternate in-frame exon in the 5' coding region, compared to variant 1. The resulting isoform (b) lacks an internal segment near the N-terminus, compared to isoform a. It is not known if this variant is targeted to the cell membrane.

Source sequence(s)

AC105186, AC129925, AY941828, BC041688

Consensus CDS

CCDS55208.1

UniProtKB/TrEMBL

B4DS89

Related

ENSP00000429979.1, ENST00000517892.5

Conserved Domains (1) summary

pfam02351
Location:146 → 242

GDNF; GDNF/GAS1 domain
NM_001165039.2 → NP_001158511.1 GDNF family receptor alpha-2 isoform c precursor

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks two alternate in-frame exons in the 5' coding region, compared to variant 1. The resulting isoform (c) lacks an internal segment near the N-terminus, compared to isoform a. It is not known if this variant is targeted to the cell membrane.

Source sequence(s)

AC105186, AC129925, AY326396, BC041688

Consensus CDS

CCDS55207.1

UniProtKB/TrEMBL

B4DS89

Related

ENSP00000429206.1, ENST00000518077.5

Conserved Domains (1) summary

pfam02351
Location:118 → 214

GDNF; GDNF/GAS1 domain
NM_001495.5 → NP_001486.4 GDNF family receptor alpha-2 isoform a preproprotein

See identical proteins and their annotated locations for NP_001486.4

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (a).

Source sequence(s)

AC105186, AC129925, BC041688

Consensus CDS

CCDS47816.1

UniProtKB/Swiss-Prot

E9PD47, O00451, O15316, O15328, Q58J92, Q6GTR9, Q7Z5C2

Related

ENSP00000428518.1, ENST00000524240.6

Conserved Domains (2) summary

smart00907
Location:40 → 113

GDNF; GDNF/GAS1 domain

pfam02351
Location:251 → 347

GDNF; GDNF/GAS1 domain