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    GABRA4 gamma-aminobutyric acid type A receptor subunit alpha4 [ Homo sapiens (human) ]

    Gene ID: 2557, updated on 14-Nov-2024

    Summary

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    Official Symbol
    GABRA4provided by HGNC
    Official Full Name
    gamma-aminobutyric acid type A receptor subunit alpha4provided by HGNC
    Primary source
    HGNC:HGNC:4078
    See related
    Ensembl:ENSG00000109158 MIM:137141; AllianceGenome:HGNC:4078
    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
    Summary
    Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. This gene encodes subunit alpha-4, which is involved in the etiology of autism and eventually increases autism risk through interaction with another subunit, gamma-aminobutyric acid receptor beta-1 (GABRB1). Alternatively spliced transcript variants encoding different isoforms have been found in this gene.[provided by RefSeq, Feb 2011]
    Expression
    Biased expression in brain (RPKM 6.9) and heart (RPKM 1.7) See more
    Orthologs
    mouse all
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    Genomic context

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    See GABRA4 in Genome Data Viewer
    Location:
    4p12
    Exon count:
    9
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 4 NC_000004.12 (46918900..46993581, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 4 NC_060928.1 (46886225..46960936, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 4 NC_000004.11 (46920917..46995598, complement)

    Chromosome 4 - NC_000004.12Genomic Context describing neighboring genes Neighboring gene H3K27ac hESC enhancer GRCh37_chr4:46725989-46726490 Neighboring gene H3K27ac hESC enhancer GRCh37_chr4:46726491-46726990 Neighboring gene Rac family small GTPase 1 pseudogene 2 Neighboring gene cytochrome c oxidase subunit 7B2 Neighboring gene ReSE screen-validated silencer GRCh37_chr4:46889421-46889608 Neighboring gene Sharpr-MPRA regulatory region 10756 Neighboring gene Sharpr-MPRA regulatory region 8016 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 21529 Neighboring gene gamma-aminobutyric acid type A receptor subunit beta1 Neighboring gene small nucleolar RNA U13 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:47379937-47380444 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15398 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr4:47416165-47416745 Neighboring gene ReSE screen-validated silencer GRCh37_chr4:47432124-47432333 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15399 Neighboring gene COMM domain containing 8

    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 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. De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy. Sajan SA, et al. Eur J Hum Genet, 2024 Aug. PMID 38565639, Free PMC Article
    2. Alternative splicing of the GABA(A) receptor alpha 4 subunit creates a severely truncated mRNA. Mu W, et al. Brain Res Bull, 2002 Sep 15. PMID 12242096
    3. Human genome search in celiac disease using gliadin cDNA as probe. Kumar R, et al. J Mol Biol, 2000 Jul 28. PMID 10903861
    4. Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site. Yang W, et al. Eur J Pharmacol, 1995 Nov 30. PMID 8719416
    5. How phenotype and developmental stage affect the genes we find: GABRA2 and impulsivity. Dick DM, et al. Twin Res Hum Genet, 2013 Jun. PMID 23561058, Free PMC Article

    See all (48) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy.
      Title: De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy.
    2. A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype.
      Title: A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype.
    3. Further evidence of GABRA4 and TOP3B as autism susceptibility genes.
      Title: Further evidence of GABRA4 and TOP3B as autism susceptibility genes.
    4. Steady-state activation of the high-affinity isoform of the alpha4beta2delta GABAA receptor.
      Title: Steady-state activation of the high-affinity isoform of the α4β2δ GABA(A) receptor.
    5. Study identified a rare noncoding sequence variants in gamma-aminobutyric acid A receptor, alpha 4 subunit in autism spectrum disorder. GABRA4 rare variants in noncoding DNA may be variants of modest physiological effects in ASD etiology.
      Title: Identification of rare noncoding sequence variants in gamma-aminobutyric acid A receptor, alpha 4 subunit in autism spectrum disorder.
    6. GABRA4 rs2229940 did not show association with migraine risk
      Title: Gamma-aminobutyric acid (GABA) receptors GABRA4, GABRE, and GABRQ gene polymorphisms and risk for migraine.
    7. These results suggest association between GABRR3 rs832032 polymorphism and the risk for restless legs syndrome , and a modifier effect of GABRA4 rs2229940 on the age of onset of restless legs syndrome .
      Title: Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome.
    8. rs505474, rs1398175, and rs4868029 in the GABRA2, GABRA4, and GABRP genes, respectively, allele frequencies were significantly different between patients and controls.Four haplotypes were significantly associated with Bipolar Disorder TA and AG for rs3815762 and rs4868029 in GABRP, GG for rs11636988 and rs8024256 in GABRB3 and GAGG for rs2197414, rs4921195, rs13188991, and rs11956731 in GABRA6.
      Title: Contribution of genes in the GABAergic pathway to bipolar disorder and its executive function deficit in the Chinese Han population.
    9. GABRA4 is associated with autism spectrum disorder in a dataset from Argentina.
      Title: Association between GABA(A) receptor subunit polymorphisms and autism spectrum disorder (ASD).
    10. The ability of neurosteroids to modulate the phosphorylation and membrane insertion of alpha4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.
      Title: Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors.
    Submit: New GeneRIF Correction See all GeneRIFs (23)

    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 search for type 2 diabetes susceptibility genes in an extended Arab family.
    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)

    Pathways from PubChem

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    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
    contributes_to GABA-A receptor activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables GABA-gated chloride ion channel activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    contributes_to benzodiazepine receptor activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    contributes_to chloride channel activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    involved_in chloride transmembrane transport IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in chloride transmembrane transport IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in gamma-aminobutyric acid signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in gamma-aminobutyric acid signaling pathway IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in gamma-aminobutyric acid signaling pathway ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in inhibitory synapse assembly IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in regulation of postsynaptic membrane potential IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in synaptic transmission, GABAergic IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in synaptic transmission, GABAergic NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    Component Evidence Code Pubs
    part_of GABA-A receptor complex IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    part_of GABA-A receptor complex IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    part_of GABA-A receptor complex ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in GABA-ergic synapse IEA
    Inferred from Electronic Annotation
    more info
    		  
    part_of chloride channel complex IEA
    Inferred from Electronic Annotation
    more info
    		  
    is_active_in dendrite membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
    		  
    is_active_in postsynapse IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in postsynaptic specialization membrane IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    gamma-aminobutyric acid receptor subunit alpha-4
    Names
    GABA(A) receptor, alpha 4
    GABAAR subunit alpha-4
    gamma-aminobutyric acid (GABA) A receptor, alpha 4
    gamma-aminobutyric acid A receptor alpha 4
    gamma-aminobutyric acid type A receptor alpha4 subunit

    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_011809.1 RefSeqGene

      Range
      4983..79664
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_000809.4 → NP_000800.2  gamma-aminobutyric acid receptor subunit alpha-4 isoform 1 precursor

      See identical proteins and their annotated locations for NP_000800.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1).
      Source sequence(s)
      AC107383, AK090780, BC037926
      Consensus CDS
      CCDS3473.1
      UniProtKB/Swiss-Prot
      P48169, Q8IYR7
      UniProtKB/TrEMBL
      X5D7F5
      Related
      ENSP00000264318.3, ENST00000264318.4
      Conserved Domains (1) summary
      cl27321
      Location:13 → 541
      Neur_chan_LBD; Neurotransmitter-gated ion-channel ligand binding domain

    2. NM_001204266.2 → NP_001191195.1  gamma-aminobutyric acid receptor subunit alpha-4 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks a segment in the first splice junction, resulting in an upstream AUG start codon, as compared to variant 1. The resulting isoform (2) has a shorter and different N-terminus, as compared to isoform 1.
      Source sequence(s)
      AC107383, BC035055, BC037926, CD013893
      UniProtKB/Swiss-Prot
      P48169
      Conserved Domains (3) summary
      TIGR00860
      Location:5 → 522
      LIC; Cation transporter family protein
      pfam02931
      Location:30 → 237
      Neur_chan_LBD; Neurotransmitter-gated ion-channel ligand binding domain
      pfam02932
      Location:244 → 519
      Neur_chan_memb; Neurotransmitter-gated ion-channel transmembrane region

    3. NM_001204267.2 → NP_001191196.1  gamma-aminobutyric acid receptor subunit alpha-4 isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks a segment in the first splice junction, resulting in an upstream AUG start codon, and lacks an in-frame exon in the middle region, as compared to variant 1. The resulting isoform (3) has a shorter and different N-terminus and lacks an internal segment, as compared to isoform 1.
      Source sequence(s)
      AC107383, BC035055, BC037926, CD013892
      UniProtKB/Swiss-Prot
      P48169
      Conserved Domains (3) summary
      TIGR00860
      Location:5 → 471
      LIC; Cation transporter family protein
      pfam02931
      Location:30 → 228
      Neur_chan_LBD; Neurotransmitter-gated ion-channel ligand binding domain
      pfam02932
      Location:222 → 468
      Neur_chan_memb; Neurotransmitter-gated ion-channel transmembrane region

    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_000004.12 Reference GRCh38.p14 Primary Assembly

      Range
      46918900..46993581 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060928.1 Alternate T2T-CHM13v2.0

      Range
      46886225..46960936 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P48169.2 GenPept UniProtKB/Swiss-Prot:P48169

    Gene LinkOut

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

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