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    P4HTM prolyl 4-hydroxylase, transmembrane [ Homo sapiens (human) ]

    Gene ID: 54681, updated on 27-Nov-2024

    Summary

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    Official Symbol
    P4HTMprovided by HGNC
    Official Full Name
    prolyl 4-hydroxylase, transmembraneprovided by HGNC
    Primary source
    HGNC:HGNC:28858
    See related
    Ensembl:ENSG00000178467 MIM:614584; AllianceGenome:HGNC:28858
    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
    PH4; PH-4; PHD4; EGLN4; HIDEA; HIFPH4; P4H-TM
    Summary
    The product of this gene belongs to the family of prolyl 4-hydroxylases. This protein is a prolyl hydroxylase that may be involved in the degradation of hypoxia-inducible transcription factors under normoxia. It plays a role in adaptation to hypoxia and may be related to cellular oxygen sensing. Alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
    Expression
    Ubiquitous expression in brain (RPKM 16.9), adrenal (RPKM 14.4) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See P4HTM in Genome Data Viewer
    Location:
    3p21.31; 3p21.3
    Exon count:
    9
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (48989908..49007153)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (49017960..49035193)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (49027341..49044586)

    Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene hESC enhancers GRCh37_chr3:48955152-48955902 and GRCh37_chr3:48955903-48956654 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:48956655-48957405 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48959089-48959589 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48961592-48962092 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48962093-48962593 Neighboring gene ARIH2 opposite strand lncRNA Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19846 Neighboring gene ariadne RBR E3 ubiquitin protein ligase 2 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19847 Neighboring gene MPRA-validated peak4646 silencer Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr3:49000975-49001622 Neighboring gene uncharacterized LOC124909376 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:49026394-49026957 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:49026958-49027520 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14344 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:49028085-49028646 Neighboring gene uncharacterized LOC124906235 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:49043602-49044590 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14345 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14346 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:49051026-49051863 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19849 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:49054789-49055560 Neighboring gene WD repeat domain 6 Neighboring gene DALR anticodon binding domain containing 3 Neighboring gene microRNA 425

    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. Biallelic Mutations in P4HTM Cause Syndromic Obesity. Saeed S, et al. Diabetes, 2023 Sep 1. PMID 37083980
    2. A pathogenic P4HTM gene variant in two brothers with autism spectrum disorder. Gülcü Üstün NS. Psychiatr Genet, 2024 Apr 1. PMID 38441145
    3. The peptide-substrate-binding domain of collagen prolyl 4-hydroxylases is a tetratricopeptide repeat domain with functional aromatic residues. Pekkala M, et al. J Biol Chem, 2004 Dec 10. PMID 15456751
    4. Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains. Myllykoski M, et al. J Biol Chem, 2021 Jan-Jun. PMID 33334883, Free PMC Article
    5. Further delineation of HIDEA syndrome. Maddirevula S, et al. Am J Med Genet A, 2020 Dec. PMID 32965080

    See all (30) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. A pathogenic P4HTM gene variant in two brothers with autism spectrum disorder.
      Title: A pathogenic P4HTM gene variant in two brothers with autism spectrum disorder.
    2. Biallelic Mutations in P4HTM Cause Syndromic Obesity.
      Title: Biallelic Mutations in P4HTM Cause Syndromic Obesity.
    3. Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains.
      Title: Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains.
    4. Further delineation of HIDEA syndrome.
      Title: Further delineation of HIDEA syndrome.
    5. The results suggest that SESN2 increases degradation of HIF-1A via AMPK-PHD regulation that contributes to inhibition of in vitro and in vivo tumorigenesis.
      Title: Sestrin2 inhibits hypoxia-inducible factor-1α accumulation via AMPK-mediated prolyl hydroxylase regulation.
    6. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours. [review]
      Title: The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration.
    7. Results suggest that increased expression of prolyl hydroxylase (PH) might play an role in the physiology of uterine leiomyoma during the menstrual cycle.
      Title: Human prolyl hydroxylase expression in uterine leiomyoma during the menstrual cycle.
    8. crystal structure of the peptide-substrate-binding domain
      Title: The peptide-substrate-binding domain of collagen prolyl 4-hydroxylases is a tetratricopeptide repeat domain with functional aromatic residues.
    9. the longest and shortest isoenzymes have major transcripts encoding inactive polypeptides, which suggest novel regulation by alternative splicing.
      Title: Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor.
    10. Data suggest that PH-4 is a novel hypoxia-inducible factor-prolyl hydroxylase that may be involved in the degradation of hypoxia-inducible transcription factors under normoxia.
      Title: Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors.
    Submit: New GeneRIF Correction See all GeneRIFs (11)

    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

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Nef nef The yeast two-hybrid screen and the coimmunoprecipitation analysis identify the HIV-1 Nef interacting human protein prolyl 4-hydroxylase (PH4) in cells PubMed

    Go to the HIV-1, Human Interaction Database

    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 2-oxoglutarate-dependent dioxygenase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables L-ascorbic acid binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables calcium ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables hypoxia-inducible factor-proline dioxygenase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables iron ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables procollagen-proline 4-dioxygenase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    Process Evidence Code Pubs
    involved_in regulation of erythrocyte differentiation IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    Component Evidence Code Pubs
    is_active_in endoplasmic reticulum IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in endoplasmic reticulum membrane IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    transmembrane prolyl 4-hydroxylase
    Names
    HIF-PH4
    HIF-prolyl hydroxylase 4
    HPH-4
    P4H with transmembrane domain
    Prolyl hydroxlase domain-containing 4
    hypoxia-inducible factor prolyl 4-hydroxylase
    hypoxia-inducible factor prolyl hydroxylase 4
    proline 4-hydroxylase
    prolyl 4-hydroxylase, transmembrane (endoplasmic reticulum)
    NP_808807.2
    NP_808808.1
    XP_047304323.1
    XP_047304324.1
    XP_054202924.1
    XP_054202925.1

    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.

    mRNA and Protein(s)

    1. NM_177938.2 → NP_808807.2  transmembrane prolyl 4-hydroxylase isoform c

      See identical proteins and their annotated locations for NP_808807.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) contains two additional segments in the coding region, compared to variant 1. The resulting isoform (c) is longer, compared to isoform a.
      Source sequence(s)
      AW072069, BC000580, BC011710, BC047566
      Consensus CDS
      CCDS2781.2
      UniProtKB/Swiss-Prot
      Q9NXG6
      Related
      ENSP00000341422.4, ENST00000343546.8
      Conserved Domains (3) summary
      smart00702
      Location:246 → 519
      P4Hc; Prolyl 4-hydroxylase alpha subunit homologues
      cd00051
      Location:194 → 252
      EFh; EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to ...
      pfam13499
      Location:192 → 252
      EF-hand_7; EF-hand domain pair

    2. NM_177939.3 → NP_808808.1  transmembrane prolyl 4-hydroxylase isoform a

      See identical proteins and their annotated locations for NP_808808.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the shortest transcript.
      Source sequence(s)
      AC137630, AW072069, BC000580, BC011710, BC047566
      Consensus CDS
      CCDS43089.1
      UniProtKB/Swiss-Prot
      Q6PAG6, Q8TCJ9, Q8WV55, Q96F22, Q9BW77, Q9NXG6
      Related
      ENSP00000373235.4, ENST00000383729.9
      Conserved Domains (3) summary
      smart00702
      Location:246 → 458
      P4Hc; Prolyl 4-hydroxylase alpha subunit homologues
      cd00051
      Location:194 → 252
      EFh; EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to ...
      pfam13499
      Location:192 → 252
      EF-hand_7; EF-hand domain pair

    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_000003.12 Reference GRCh38.p14 Primary Assembly

      Range
      48989908..49007153
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047448367.1 → XP_047304323.1  transmembrane prolyl 4-hydroxylase isoform X1

    2. XM_047448368.1 → XP_047304324.1  transmembrane prolyl 4-hydroxylase isoform X2

    RNA

    1. XR_007095696.1 RNA Sequence

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060927.1 Alternate T2T-CHM13v2.0

      Range
      49017960..49035193
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054346949.1 → XP_054202924.1  transmembrane prolyl 4-hydroxylase isoform X1

    2. XM_054346950.1 → XP_054202925.1  transmembrane prolyl 4-hydroxylase isoform X2

    RNA

    1. XR_008486738.1 RNA Sequence

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_017732.3: Suppressed sequence

      Description
      NM_017732.3: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9NXG6.2 GenPept UniProtKB/Swiss-Prot:Q9NXG6

    Gene LinkOut

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

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