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    PITX2 paired like homeodomain 2 [ Homo sapiens (human) ]

    Gene ID: 5308, updated on 10-Dec-2024

    Summary

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    Official Symbol
    PITX2provided by HGNC
    Official Full Name
    paired like homeodomain 2provided by HGNC
    Primary source
    HGNC:HGNC:9005
    See related
    Ensembl:ENSG00000164093 MIM:601542; AllianceGenome:HGNC:9005
    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
    RS; RGS; ARP1; Brx1; IDG2; IGDS; IHG2; PTX2; RIEG; ASGD4; IGDS2; IRID2; Otlx2; RIEG1
    Summary
    This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]
    Expression
    Biased expression in placenta (RPKM 15.1), urinary bladder (RPKM 3.5) and 6 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See PITX2 in Genome Data Viewer
    Location:
    4q25
    Exon count:
    9
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 4 NC_000004.12 (110617423..110642123, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 4 NC_060928.1 (113919284..113943981, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 4 NC_000004.11 (111538579..111563279, complement)

    Chromosome 4 - NC_000004.12Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid active region 21817 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_72001 Neighboring gene glutamyl aminopeptidase Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_72004 Neighboring gene Sharpr-MPRA regulatory region 9284 Neighboring gene uncharacterized LOC105377363 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr4:111537217-111537875 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:111540229-111540882 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:111540883-111541534 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:111542189-111542841 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15630 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr4:111547605-111548106 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr4:111548107-111548606 Neighboring gene NANOG-H3K4me1 hESC enhancer GRCh37_chr4:111549504-111550355 Neighboring gene PITX2 adjacent non-coding RNA Neighboring gene H3K4me1 hESC enhancer GRCh37_chr4:111553473-111553985 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr4:111559017-111559517 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr4:111560253-111560848 Neighboring gene NANOG-H3K4me1 hESC enhancer GRCh37_chr4:111562143-111562646 Neighboring gene uncharacterized LOC124900857 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:111614011-111614566 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_72035 Neighboring gene VISTA enhancer hs930 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr4:111715278-111715811 Neighboring gene microRNA 297

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: Tissue-specific circular RNA induction during human fetal development
    • Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
    • BioProject: PRJNA270632
    • Publication: PMID 26076956
    • Analysis date: Mon Apr 2 22:54:59 2018

    Bibliography

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    Related articles in PubMed

    1. PITX2 DNA Methylation as Biomarker for Individualized Risk Assessment of Prostate Cancer in Core Biopsies. Uhl B, et al. J Mol Diagn, 2017 Jan. PMID 27939865
    2. PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome. Zhao CM, et al. PLoS One, 2015. PMID 25893250, Free PMC Article
    3. Usefulness of single nucleotide polymorphism in chromosome 4q25 to predict in-hospital and long-term development of atrial fibrillation and survival in patients undergoing coronary artery bypass grafting. Virani SS, et al. Am J Cardiol, 2011 May 15. PMID 21414601, Free PMC Article
    4. Truncation of PITX2 differentially affects its activity on physiological targets. Quentien MH, et al. J Mol Endocrinol, 2011 Feb. PMID 20978111
    5. Paired-like Homeodomain Transcription factor 2 expression by breast cancer bone marrow disseminated tumor cells is associated with early recurrent disease development. Pillai SG, et al. Breast Cancer Res Treat, 2015 Oct. PMID 26400846, Free PMC Article

    See all (225) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis.
      Title: PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis.
    2. Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2.
      Title: Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2.
    3. Exploring the association between PITX2, third molars agenesis and sella turcica morphology : PITX2, third molars agenesis and sella turcica morphology.
      Title: Exploring the association between PITX2, third molars agenesis and sella turcica morphology : PITX2, third molars agenesis and sella turcica morphology.
    4. Enamel defects of Axenfeld-Rieger syndrome and the role of PITX2 in its pathogenesis.
      Title: Enamel defects of Axenfeld-Rieger syndrome and the role of PITX2 in its pathogenesis.
    5. Pulmonary Vein Myocardial Sleeve Length and its Association With Sex and 4q25/PITX2 Genotype.
      Title: Pulmonary Vein Myocardial Sleeve Length and its Association With Sex and 4q25/PITX2 Genotype.
    6. PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation.
      Title: PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation.
    7. PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.
      Title: PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.
    8. Association Between rs2200733 Polymorphism of PITX2 Gene and the Risk of Atrial Fibrillation.
      Title: Association Between rs2200733 Polymorphism of PITX2 Gene and the Risk of Atrial Fibrillation.
    9. Genotype-phenotype association of PITX2 and FOXC1 in Axenfeld-Rieger syndrome.
      Title: Genotype-phenotype association of PITX2 and FOXC1 in Axenfeld-Rieger syndrome.
    10. Comparison of Anterior Segment Abnormalities in Individuals With FOXC1 and PITX2 Variants.
      Title: Comparison of Anterior Segment Abnormalities in Individuals With FOXC1 and PITX2 Variants.
    Submit: New GeneRIF Correction See all GeneRIFs (171)

    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
    Anophthalmia-microphthalmia syndrome
    MedGen: C5680330 GeneReviews: Not available
    		Compare labs
    Anterior segment dysgenesis 4
    MedGen: C1842031 OMIM: 137600 GeneReviews: Not available
    		Compare labs
    Axenfeld-Rieger syndrome type 1
    MedGen: C3714873 OMIM: 180500 GeneReviews: Not available
    		Compare labs
    Ring dermoid of cornea
    MedGen: C1867155 OMIM: 180550 GeneReviews: Not available
    		Compare labs

    Copy number response

    Description
    Copy number response
    Triplosensitivity

    No evidence available (Last evaluated 2022-10-24)

    ClinGen Genome Curation Page
    Haploinsufficency

    Sufficient evidence for dosage pathogenicity (Last evaluated 2022-10-24)

    ClinGen Genome Curation PagePubMed

    EBI GWAS Catalog

    Description
    Common variants in KCNN3 are associated with lone atrial fibrillation.
    EBI GWAS Catalog
    Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.
    EBI GWAS Catalog
    Meta-analysis identifies six new susceptibility loci for atrial fibrillation.
    EBI GWAS Catalog
    Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.
    EBI GWAS Catalog
    Variants conferring risk of atrial fibrillation on chromosome 4q25.
    EBI GWAS Catalog
    Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.
    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

    Clone Names

    • MGC20144, MGC111022

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables DNA-binding transcription factor activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables DNA-binding transcription factor activity, RNA polymerase II-specific IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables DNA-binding transcription factor activity, RNA polymerase II-specific IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables DNA-binding transcription factor activity, RNA polymerase II-specific ISA
    Inferred from Sequence Alignment
    more info
    		  
    enables DNA-binding transcription factor binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables DNA-binding transcription repressor activity, RNA polymerase II-specific IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables RNA polymerase II cis-regulatory region sequence-specific DNA binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables RNA polymerase II-specific DNA-binding transcription factor binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables identical protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables phosphoprotein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein homodimerization activity IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables ribonucleoprotein complex binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables sequence-specific double-stranded DNA binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables transcription cis-regulatory region binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in anatomical structure morphogenesis IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in camera-type eye development IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in cardiac neural crest cell migration involved in outflow tract morphogenesis ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in deltoid tuberosity development IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in determination of left/right symmetry ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in embryonic heart tube left/right pattern formation ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in hair cell differentiation IC
    Inferred by Curator
    more info
    		 PubMed 
    involved_in iris morphogenesis IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in left/right axis specification ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in negative regulation of transcription by RNA polymerase II IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in negative regulation of transcription by RNA polymerase II IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in odontogenesis IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in outflow tract morphogenesis ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in positive regulation of cell population proliferation ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in positive regulation of transcription by RNA polymerase II IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in prolactin secreting cell differentiation TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in regulation of DNA-templated transcription IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in regulation of transcription by RNA polymerase II IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    acts_upstream_of_or_within regulation of transcription by RNA polymerase II IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in somatotropin secreting cell differentiation TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in spleen development ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    Component Evidence Code Pubs
    located_in chromatin ISA
    Inferred from Sequence Alignment
    more info
    		  
    located_in cytoplasm IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
    		  
    located_in nucleoplasm TAS
    Traceable Author Statement
    more info
    		  
    is_active_in nucleus IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in nucleus IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    part_of transcription regulator complex IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    pituitary homeobox 2
    Names
    ALL1-responsive protein ARP1
    all1-responsive gene 1
    homeobox protein PITX2
    paired-like homeodomain transcription factor 2
    rieg bicoid-related homeobox transcription factor 1
    solurshin

    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_007120.1 RefSeqGene

      Range
      19276..24930
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_000325.6 → NP_000316.2  pituitary homeobox 2 isoform c

      See identical proteins and their annotated locations for NP_000316.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3), also known as ARP1c, lacks several exons at the 5' end and has an alternate 5' exon, as compared to variant 2. The resulting isoform (c) has a longer and distinct N-terminus, as compared to isoform b.
      Source sequence(s)
      AC017068, BC013998
      Consensus CDS
      CCDS3694.1
      UniProtKB/TrEMBL
      A0A8J9C2I7
      Related
      ENSP00000495061.1, ENST00000644743.1
      Conserved Domains (3) summary
      COG5576
      Location:40 → 149
      COG5576; Homeodomain-containing transcription factor [Transcription]
      pfam00046
      Location:96 → 149
      Homeobox; Homeobox domain
      pfam03826
      Location:282 → 299
      OAR; OAR domain

    2. NM_001204397.2 → NP_001191326.1  pituitary homeobox 2 isoform b

      See identical proteins and their annotated locations for NP_001191326.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) has an additional exon in the 5' UTR, as compared to variant 2. Variants 2, 4 and 5 encode the same isoform b.
      Source sequence(s)
      AC017068
      Consensus CDS
      CCDS3692.1
      UniProtKB/Swiss-Prot
      A8K6C6, B2RA02, B3KXS0, O60578, O60579, O60580, Q3KQX9, Q99697, Q9BY17
      UniProtKB/TrEMBL
      D6RFI4
      Related
      ENSP00000347004.2, ENST00000354925.6
      Conserved Domains (2) summary
      pfam00046
      Location:89 → 142
      Homeobox; Homeobox domain
      pfam03826
      Location:275 → 292
      OAR; OAR domain

    3. NM_001204398.1 → NP_001191327.1  pituitary homeobox 2 isoform b

      See identical proteins and their annotated locations for NP_001191327.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) lacks an exon in the 5' UTR, as compared to variant 2. Variants 2, 4 and 5 encode the same isoform b.
      Source sequence(s)
      BC106010, BP372081
      Consensus CDS
      CCDS3692.1
      UniProtKB/Swiss-Prot
      A8K6C6, B2RA02, B3KXS0, O60578, O60579, O60580, Q3KQX9, Q99697, Q9BY17
      UniProtKB/TrEMBL
      D6RFI4
      Related
      ENSP00000421454.1, ENST00000511837.5
      Conserved Domains (2) summary
      pfam00046
      Location:89 → 142
      Homeobox; Homeobox domain
      pfam03826
      Location:275 → 292
      OAR; OAR domain

    4. NM_001204399.1 → NP_001191328.1  pituitary homeobox 2 isoform a

      See identical proteins and their annotated locations for NP_001191328.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) lacks an exon in the 5' UTR and an in-frame exon in the 5' CDS, as compared to variant 2. The resulting isoform (a) lacks an internal segment, as compared to isoform b. Variants 1 and 6 encode the same isoform a.
      Source sequence(s)
      BC106010, BP372081
      Consensus CDS
      CCDS3693.1
      UniProtKB/TrEMBL
      A0A8J9C2I7
      Conserved Domains (2) summary
      pfam00046
      Location:43 → 96
      Homeobox; Homeobox domain
      pfam03826
      Location:229 → 246
      OAR; OAR domain

    5. NM_153426.3 → NP_700475.1  pituitary homeobox 2 isoform b

      See identical proteins and their annotated locations for NP_700475.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2), also known as ARP1b, encodes the predominant isoform (b).
      Source sequence(s)
      AC017068
      Consensus CDS
      CCDS3692.1
      UniProtKB/Swiss-Prot
      A8K6C6, B2RA02, B3KXS0, O60578, O60579, O60580, Q3KQX9, Q99697, Q9BY17
      UniProtKB/TrEMBL
      D6RFI4
      Related
      ENSP00000378095.4, ENST00000394595.8
      Conserved Domains (2) summary
      pfam00046
      Location:89 → 142
      Homeobox; Homeobox domain
      pfam03826
      Location:275 → 292
      OAR; OAR domain

    6. NM_153427.3 → NP_700476.1  pituitary homeobox 2 isoform a

      See identical proteins and their annotated locations for NP_700476.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1), also known as ARP1a, lacks an in-frame exon in the 5' region, as compared to variant 2. The resulting isoform (a) lacks an internal segment, as compared to isoform b. Variants 1 and 6 encode the same isoform a.
      Source sequence(s)
      AC017068
      Consensus CDS
      CCDS3693.1
      UniProtKB/TrEMBL
      A0A8J9C2I7
      Related
      ENSP00000347192.5, ENST00000355080.9
      Conserved Domains (2) summary
      pfam00046
      Location:43 → 96
      Homeobox; Homeobox domain
      pfam03826
      Location:229 → 246
      OAR; OAR 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_000004.12 Reference GRCh38.p14 Primary Assembly

      Range
      110617423..110642123 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_024454090.2 → XP_024309858.1  pituitary homeobox 2 isoform X1

      Related
      ENST00000645131.1
      Conserved Domains (2) summary
      pfam00046
      Location:2 → 31
      Homeobox; Homeobox domain
      pfam03826
      Location:164 → 181
      OAR; OAR domain

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060928.1 Alternate T2T-CHM13v2.0

      Range
      113919284..113943981 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054350186.1 → XP_054206161.1  pituitary homeobox 2 isoform X1

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q99697.2 GenPept UniProtKB/Swiss-Prot:Q99697

    Gene LinkOut

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

    Chemical Information
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