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    CTLA4 cytotoxic T-lymphocyte associated protein 4 [ Homo sapiens (human) ]

    Gene ID: 1493, updated on 29-Oct-2024

    Summary

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    Official Symbol
    CTLA4provided by HGNC
    Official Full Name
    cytotoxic T-lymphocyte associated protein 4provided by HGNC
    Primary source
    HGNC:HGNC:2505
    See related
    Ensembl:ENSG00000163599 MIM:123890; AllianceGenome:HGNC:2505
    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
    CD; GSE; GRD4; ALPS5; CD152; CTLA-4; IDDM12; CELIAC3
    Summary
    This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases. [provided by RefSeq, Jul 2008]
    Expression
    Biased expression in lymph node (RPKM 10.3), appendix (RPKM 9.7) and 8 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See CTLA4 in Genome Data Viewer
    Location:
    2q33.2
    Exon count:
    4
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (203867771..203873965)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (204349656..204355847)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (204732494..204738688)

    Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene nucleophosmin 1 pseudogene 33 Neighboring gene RNA, U6 small nuclear 474, pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid active region 17014 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 17015 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr2:204675919-204677118 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 17016 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 12259 Neighboring gene uncharacterized LOC101927840 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr2:204808046-204809245 Neighboring gene inducible T cell costimulator Neighboring gene ATAC-STARR-seq lymphoblastoid active region 17017 Neighboring gene zinc finger protein 555 pseudogene

    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. Expression of CD152 (CTLA-4) in children with autoimmune thyroiditis and +49 A/G polymorphism of exon 1 of the CTLA-4 gene. Kucharska AM, et al. J Physiol Pharmacol, 2009 Nov. PMID 20134044
    2. Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. Joshita S, et al. J Hepatol, 2010 Sep. PMID 20557968
    3. CTLA-4 gene polymorphism +49 A/G contributes to genetic susceptibility to two infection-related cancers-hepatocellular carcinoma and cervical cancer. Hu L, et al. Hum Immunol, 2010 Sep. PMID 20538028
    4. CTLA4 CT60 single-nucleotide polymorphism is associated with Slovenian inflammatory bowel disease patients and regulates expression of CTLA4 isoforms. Repnik K, et al. DNA Cell Biol, 2010 Oct. PMID 20491567
    5. CTLA4 -1661A/G and 3'UTR long repeat polymorphisms are associated with ulcerative colitis and influence CTLA4 mRNA and protein expression. Chen Z, et al. Genes Immun, 2010 Oct. PMID 20445568

    See all (1000) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients.
      Title: Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients.
    2. Association of four CTLA-4 gene polymorphisms with pemphigus risk: a systematic review, meta-analysis, and meta-regression.
      Title: Association of four CTLA-4 gene polymorphisms with pemphigus risk: a systematic review, meta-analysis, and meta-regression.
    3. Decoding the genetic influence of CT60 non-coding polymorphism in CTLA-4 gene and sCTLA-4 biomarker with rheumatoid arthritis in the Indian population.
      Title: Decoding the genetic influence of CT60 non-coding polymorphism in CTLA-4 gene and sCTLA-4 biomarker with rheumatoid arthritis in the Indian population.
    4. Cytotoxic T-lymphocyte associated protein 4 (CTLA4) polymorphisms are linked to systemic lupus erythematosus: an updated meta-analysis.
      Title: Cytotoxic T-lymphocyte associated protein 4 (CTLA4) polymorphisms are linked to systemic lupus erythematosus: an updated meta-analysis.
    5. Effect of DNA methylation at the CTLA4 gene on the clinical status of autoimmune thyroid diseases.
      Title: Effect of DNA methylation at the CTLA4 gene on the clinical status of autoimmune thyroid diseases.
    6. Prognostic effect of CTLA4/LAG3 Expression by T-Cells Subsets on Acute Myeloid Leukemia Patients.
      Title: Prognostic effect of CTLA4/LAG3 Expression by T-Cells Subsets on Acute Myeloid Leukemia Patients.
    7. Relationship Between Cytotoxic T-Lymphocyte-associated Antigen-4: Programmed Death-1 Genes Polymorphisms and Susceptibility to Pediatric B-Cell Acute Lymphoblastic Leukemia.
      Title: Relationship Between Cytotoxic T-Lymphocyte-associated Antigen-4: Programmed Death-1 Genes Polymorphisms and Susceptibility to Pediatric B-Cell Acute Lymphoblastic Leukemia.
    8. [Association of CTLA-4 gene polymorphisms with the genetic susceptibility and prognosis of patients with Bladder urothelial carcinoma].
      Title: [Association of CTLA-4 gene polymorphisms with the genetic susceptibility and prognosis of patients with Bladder urothelial carcinoma].
    9. CTLA-4 silencing could promote anti-tumor effects in hepatocellular.
      Title: CTLA-4 silencing could promote anti-tumor effects in hepatocellular.
    10. Targeting the dynamic transcriptional landscape of Treg subpopulations in pancreatic ductal adenocarcinoma: Insights from single-cell RNA sequencing analysis with a focus on CTLA4 and TIGIT.
      Title: Targeting the dynamic transcriptional landscape of Treg subpopulations in pancreatic ductal adenocarcinoma: Insights from single-cell RNA sequencing analysis with a focus on CTLA4 and TIGIT.
    Submit: New GeneRIF Correction See all GeneRIFs (1043)

    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

    Associated conditions

    Description Tests
    Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
    MedGen: C4015214 OMIM: 616100 GeneReviews: Not available
    		Compare labs
    Celiac disease, susceptibility to, 3
    MedGen: C1857845 OMIM: 609755 GeneReviews: Not available
    		Compare labs
    Hashimoto thyroiditis
    MedGen: C0677607 OMIM: 140300 GeneReviews: Not available
    		Compare labs
    Systemic lupus erythematosus
    MedGen: C0024141 OMIM: 152700 GeneReviews: Not available
    		Compare labs
    Type 1 diabetes mellitus 12
    MedGen: C1832392 OMIM: 601388 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    A genome-wide association study identifies two new risk loci for Graves' disease.
    EBI GWAS Catalog
    Genetics of rheumatoid arthritis contributes to biology and drug discovery.
    EBI GWAS Catalog
    Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.
    EBI GWAS Catalog
    Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.
    EBI GWAS Catalog
    Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
    EBI GWAS Catalog
    Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.
    EBI GWAS Catalog
    Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci.
    EBI GWAS Catalog
    Multiple common variants for celiac disease influencing immune gene expression.
    EBI GWAS Catalog
    Novel associations for hypothyroidism include known autoimmune risk loci.
    EBI GWAS Catalog
    REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.
    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)

    Genotypes

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp160, precursor env HIV-1 Env co-localizes with CTLA4 in HIV-1 infected CD4+ T cells PubMed
    env The envelope glycoprotein (gp160)) of HIV-1 is directed to intracellular CTLA-4-containing granules rather than trafficking constitutively from the Golgi to the cell surface PubMed
    Nef nef HIV-1 Nef-mediated CTLA-4 downregulation is associated with upregulation of IL-2 production in infected primary CD4+ T-cells PubMed
    nef HIV-1 Nef downregulates CTLA-4 in 293T cells and infected primary CD4+ T-cells. The Nef-induced downregulation of CTLA-4 requires the EE155, LL165, and DD175 motifs in Nef PubMed
    nef HIV-1 Nef co-localizes with CTLA-4 in early and recycling endosomes with transferrin marker protein in HeLa cells PubMed
    nef HIV-1 Nef expression in Jurkat cells upregulates the level of CTLA4 production in the absence of CD3 and CD28 stimulation PubMed
    Vpr vpr HIV-1 Vpr increases the levels of CTLA4 expression in infected T cells PubMed

    Go to the HIV-1, Human Interaction Database

    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
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in B cell receptor signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in B cell receptor signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in DNA damage response IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in T cell receptor signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in adaptive immune response IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in immune response TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in negative regulation of B cell proliferation IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in negative regulation of T cell proliferation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in negative regulation of regulatory T cell differentiation IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in negative regulation of regulatory T cell differentiation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of apoptotic process IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in Golgi apparatus IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in clathrin-coated endocytic vesicle IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    is_active_in external side of plasma membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in external side of plasma membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in perinuclear region of cytoplasm IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in plasma membrane IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
    		  
    part_of protein complex involved in cell adhesion IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    cytotoxic T-lymphocyte protein 4
    Names
    celiac disease 3
    cytotoxic T lymphocyte associated antigen 4 short spliced form
    cytotoxic T-lymphocyte-associated serine esterase-4
    gluten-sensitive enteropathy
    insulin-dependent diabetes mellitus 12
    ligand and transmembrane spliced cytotoxic T lymphocyte associated antigen 4

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    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_011502.1 RefSeqGene

      Range
      4986..11180
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_1220

    mRNA and Protein(s)

    1. NM_001037631.3 → NP_001032720.1  cytotoxic T-lymphocyte protein 4 isoform CTLA-4delTM precursor

      See identical proteins and their annotated locations for NP_001032720.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an exon in the coding region, which results in a frameshift and an early stop codon, compared to variant 1. The encoded isoform CTLA-4delTM (also known as sCTLA4) is soluble and lacks the transmembrane domain, compared to isoform a. The exon skip represented in this variant is is based on human U90273.1, and is consistent with mouse U90270.1 and the data published in PMID:10831323 and PMID:10556814.
      Source sequence(s)
      AC010138, AF414120, AI733018
      Consensus CDS
      CCDS42803.1
      UniProtKB/TrEMBL
      Q8TDA6
      Related
      ENSP00000295854.6, ENST00000295854.10
      Conserved Domains (1) summary
      cd05721
      Location:39 → 152
      IgV_CTLA-4; Immunoglobulin (Ig) domain of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)

    2. NM_005214.5 → NP_005205.2  cytotoxic T-lymphocyte protein 4 isoform CTLA4-TM precursor

      See identical proteins and their annotated locations for NP_005205.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer membrane-bound isoform CTLA4-TM.
      Source sequence(s)
      AC010138, AF414120, AI733018
      Consensus CDS
      CCDS2362.1
      UniProtKB/Swiss-Prot
      A0N1S0, E9PDH0, O95653, P16410, Q0PP65, Q52MC1, Q53TD5, Q5S005, Q8WXJ1, Q96P43, Q9UKN9
      UniProtKB/TrEMBL
      Q6GR94
      Related
      ENSP00000497102.1, ENST00000648405.2
      Conserved Domains (1) summary
      cd05721
      Location:39 → 152
      IgV_CTLA-4; Immunoglobulin (Ig) domain of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)

    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_000002.12 Reference GRCh38.p14 Primary Assembly

      Range
      203867771..203873965
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060926.1 Alternate T2T-CHM13v2.0

      Range
      204349656..204355847
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P16410.3 GenPept UniProtKB/Swiss-Prot:P16410

    Gene LinkOut

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

    Chemical Information
    Molecular Biology Databases
    Research Materials
    Tools
    Miscellaneous