P4HTM Gene

Name	prolyl 4-hydroxylase, transmembrane (endoplasmic reticulum)
Description	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]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nP4HTM encodes an atypical transmembrane prolyl 4‐hydroxylase that functions as part of the oxygen‐sensing machinery by hydroxylating specific proline residues on hypoxia‐inducible factor (HIF) α subunits. Under normoxic conditions, such hydroxylation marks HIF-α for proteasomal degradation, thereby contributing to cellular adaptation to oxygen availability. A novel form of this enzyme, originally identified as PH-4, is characterized by an N-terminal EF-hand motif linked to its catalytic domain and is localized to the endoplasmic reticulum. This localization and structure suggest that P4HTM integrates oxygen sensing with potential regulation by Ca2+ signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have further established that disruptive, biallelic variants in P4HTM underlie HIDEA syndrome—a condition characterized by hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities. Despite variable expressivity, consistent features such as cognitive impairment and hypotonia highlight the enzyme’s critical role in neurodevelopment and systemic physiology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent structural investigations of soluble human P4H-TM reveal that, in addition to the conserved catalytic core seen in other prolyl 4-hydroxylases, it harbors a distinctive EF-hand domain with two Ca2+-binding sites. The arrangement of the catalytic and EF domains forms a substrate-binding groove whose conserved residues, as well as unique surface features, point to a tailored mechanism for substrate recognition and a regulatory crosstalk between Ca2+ levels and enzymatic activity in the endoplasmic reticulum."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in oxygen sensing, emerging evidence indicates that P4HTM is implicated in metabolic regulation. Rare and novel homozygous missense mutations in P4HTM have been linked with a recessive form of severe childhood obesity, often accompanied by hypotonia, developmental delay, and, in some cases, early mortality. These findings suggest that disrupted hydroxylase activity may impact energy homeostasis and other adaptive responses related to hypoxia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, the expanding clinical spectrum of P4HTM deficiency now appears to include neurodevelopmental disorders such as autism spectrum disorder, as evidenced by reports of affected individuals with co‐occurring autistic features. This observation reinforces the significance of P4HTM in both developmental and systemic contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Felix Oehme, Peter Ellinghaus, Peter Kolkhof, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(02)00862-8"}], "href": "https://doi.org/10.1016/s0006-291x(02"}, {"type": "t", "text": "00862-8) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12163023"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12163023"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sateesh Maddirevula, Tawfeg Ben-Omran, Mariam AlMureikhi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Further delineation of HIDEA syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.61885"}], "href": "https://doi.org/10.1002/ajmg.a.61885"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32965080"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32965080"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Matti Myllykoski, Aleksi Sutinen, M Kristian Koski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA120.016542"}], "href": "https://doi.org/10.1074/jbc.RA120.016542"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33334883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33334883"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sadia Saeed, Lijiao Ning, Alaa Badreddine, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biallelic Mutations in P4HTM Cause Syndromic Obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db22-1017"}], "href": "https://doi.org/10.2337/db22-1017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37083980"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37083980"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Nur Seda Gülcü Üstün "}, {"type": "b", "children": [{"type": "t", "text": "A pathogenic P4HTM gene variant in two brothers with autism spectrum disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Psychiatr Genet (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/YPG.0000000000000364"}], "href": "https://doi.org/10.1097/YPG.0000000000000364"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38441145"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38441145"}]}]}]}
Synonyms	PH-4, EGLN4, P4H-TM, PH4, PHD4, HIFPH4
Proteins	P4HTM_HUMAN
NCBI Gene ID	54681
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

P4HTM has 8,274 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 110 datasets.

Click the + buttons to view associations for P4HTM from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

P4HTM Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of P4HTM gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of P4HTM gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of P4HTM gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of P4HTM gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of P4HTM gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of P4HTM gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of P4HTM gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of P4HTM gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of P4HTM gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of P4HTM gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of P4HTM gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of P4HTM gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with P4HTM protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with P4HTM gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of P4HTM gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of P4HTM gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of P4HTM gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of P4HTM gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing P4HTM protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing P4HTM protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with P4HTM protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with P4HTM protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of P4HTM gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with P4HTM gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with P4HTM gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with P4HTM gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of P4HTM protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by P4HTM gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving P4HTM gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with P4HTM gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with P4HTM gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with P4HTM gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with P4HTM gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with P4HTM gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for P4HTM protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at P4HTM gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of P4HTM gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of P4HTM gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing P4HTM from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of P4HTM gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.