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

    Gene ID: 2675, updated on 9-Dec-2024

    Summary

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    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

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    See GFRA2 in Genome Data Viewer
    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_000008.11Genomic Context describing neighboring genes Neighboring gene long intergenic non-protein coding RNA 3093 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr8:21227350-21227872 Neighboring gene ReSE screen-validated silencer GRCh37_chr8:21323916-21324086 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr8:21349495-21350694 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_102756 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:21406697-21407198 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:21407199-21407698 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr8:21417498-21418697 Neighboring gene uncharacterized LOC107986922 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr8:21507398-21507984 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:21550331-21550831 Neighboring gene H3K27ac hESC enhancer GRCh37_chr8:21584471-21584972 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_102784 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_102790 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:21625596-21626586 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr8:21639775-21640276 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr8:21683000-21683544 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr8:21683545-21684088 Neighboring gene olfactory receptor family 6 subfamily R member 2 pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid active region 27067 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 27068 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18973 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:21761370-21762198 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 27069 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 18974 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr8:21802075-21802708 Neighboring gene uncharacterized LOC124901903 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:21806752-21807252 Neighboring gene docking protein 2 Neighboring gene exportin 7

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • 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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    Related articles in PubMed

    1. Expression of the pituitary stem/progenitor marker GFRα2 in human pituitary adenomas and normal pituitary. Mathioudakis N, et al. Pituitary, 2015 Feb. PMID 24402129, Free PMC Article
    2. Glial cell line-derived neurotrophic factor receptor alpha 2 (GFRA2) gene is associated with tardive dyskinesia. Souza RP, et al. Psychopharmacology (Berl), 2010 Jun. PMID 20369355
    3. Cloning and characterization of the human GFRA2 locus and investigation of the gene in Hirschsprung disease. Vanhorne JB, et al. Hum Genet, 2001 May. PMID 11409869
    4. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Pottier C, et al. Lancet Neurol, 2018 Jun. PMID 29724592, Free PMC Article
    5. GDNF family receptor alpha 2 promotes neuroblastoma cell proliferation by interacting with PTEN. Li Z, et al. Biochem Biophys Res Commun, 2019 Mar 12. PMID 30722993

    See all (39) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. GFRA2 variants associated with diabetic neuropathic pain.
      Title: A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.
    8. 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.
    9. 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.
    10. 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
    Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease.
    EBI GWAS Catalog
    Genome-wide meta-analysis identifies new susceptibility loci for migraine.
    EBI GWAS Catalog

    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

    Homology

    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

    1. NG_029215.3 RefSeqGene

      Range
      28470..126947
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. 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

    2. 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

    3. 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

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000008.11 Reference GRCh38.p14 Primary Assembly

      Range
      21690398..21812345 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047421687.1 → XP_047277643.1  GDNF family receptor alpha-2 isoform X1

      UniProtKB/Swiss-Prot
      E9PD47, O00451, O15316, O15328, Q58J92, Q6GTR9, Q7Z5C2
      Related
      ENSP00000429445.1, ENST00000517328.5

    2. XM_006716327.4 → XP_006716390.1  GDNF family receptor alpha-2 isoform X1

      See identical proteins and their annotated locations for XP_006716390.1

      UniProtKB/Swiss-Prot
      E9PD47, O00451, O15316, O15328, Q58J92, Q6GTR9, Q7Z5C2
      Conserved Domains (2) summary
      smart00907
      Location:40 → 113
      GDNF; GDNF/GAS1 domain
      pfam02351
      Location:251 → 347
      GDNF; GDNF/GAS1 domain

    3. XM_011544484.3 → XP_011542786.1  GDNF family receptor alpha-2 isoform X1

      See identical proteins and their annotated locations for XP_011542786.1

      UniProtKB/Swiss-Prot
      E9PD47, O00451, O15316, O15328, Q58J92, Q6GTR9, Q7Z5C2
      Conserved Domains (2) summary
      smart00907
      Location:40 → 113
      GDNF; GDNF/GAS1 domain
      pfam02351
      Location:251 → 347
      GDNF; GDNF/GAS1 domain

    4. XM_024447127.2 → XP_024302895.1  GDNF family receptor alpha-2 isoform X2

      UniProtKB/TrEMBL
      B4DS89
      Conserved Domains (1) summary
      pfam02351
      Location:180 → 276
      GDNF; GDNF/GAS1 domain

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060932.1 Alternate T2T-CHM13v2.0

      Range
      21961568..22086203 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054360282.1 → XP_054216257.1  GDNF family receptor alpha-2 isoform X1

    2. XM_054360280.1 → XP_054216255.1  GDNF family receptor alpha-2 isoform X1

    3. XM_054360281.1 → XP_054216256.1  GDNF family receptor alpha-2 isoform X1

    4. XM_054360283.1 → XP_054216258.1  GDNF family receptor alpha-2 isoform X2

      UniProtKB/TrEMBL
      B4DS89
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    O00451.2 GenPept UniProtKB/Swiss-Prot:O00451

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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