EGLN1 — Egl-9 Family Prolyl Hydroxylase 1

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EGLN1 — Egl-9 Family Prolyl Hydroxylase 1

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EGLN1 — Egl-9 Family Prolyl Hydroxylase 1

Overview

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EGLN1 — Egl-9 Family Prolyl Hydroxylase 1

Overview

Mermaid diagram (expand to render)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EGLN1 — Egl-9 Family Prolyl Hydroxylase 1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>EGLN1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Egl-9 Family Prolyl Hydroxylase 1</td>
</tr>
<tr>
<td class="label">Previous Names</td>
<td>PHD2, EGLN1, PHD1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1q42.12</td>
</tr>
<tr>
<td class="label">Gene ID</td>
<td>54583</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000127837</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y2H5</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>609424</td>
</tr>
<tr>
<td class="label">Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Cortex</td>
<td>High</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="label">Substantia nigra</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">VHL</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">HIF-1alpha</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">HIF-2alpha</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">PHD1/3</td>
<td>Redundancy</td>
</tr>
<tr>
<td class="label">FIH1</td>
<td>Cofactor sensing</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">8 edges</a></td>
</tr>
</table>

EGLN1 (Egl-9 Family Prolyl Hydroxylase 1) encodes Prolyl Hydroxylase 2 (PHD2), the principal oxygen sensor regulating hypoxia-inducible factor-alpha (HIF-alpha) stability. EGLN1 is the most important prolyl hydroxylase for HIF regulation under physiological conditions and serves as a critical link between cellular oxygen sensing and adaptive gene expression. Variants in EGLN1 cause congenital erythrocytosis (polycythemia) and have been implicated in Alzheimer's disease and Parkinson's disease through dysregulated hypoxia response pathways["@phd2_major"][@hif_ad].

Gene Overview

Protein Structure

Domain Architecture

PHD2 is a ~426 amino acid protein with a catalytic domain and regulatory regions:

N-terminal domain: Substrate binding and oxygen sensing
catalytic core: Contains the 2-oxoglutarate (2-OG) binding site
C-terminal region: Regulatory functions and VHL interaction

Catalytic Mechanism

PHD2 is a 2-oxoglutarate (2-OG)-dependent dioxygenase that requires:

Iron (Fe²⁺): Essential cofactor in the active site
2-oxoglutarate: Cosubstrate converted to succinate
Molecular oxygen: Substrate for hydroxylation
Ascorbate: Reducing agent for iron

The reaction:
HIF-α + O₂ + 2-OG → HIF-α(OH) + succinate + CO₂

Regulatory Features

PHD2 activity is modulated by:

Oxygen concentration: Direct sensing mechanism

Iron availability: Essential cofactor

2-OG levels: Metabolic status indicator

Succinate accumulation: Product inhibition

Nitric oxide: Negative regulation

Reactive oxygen species: Oxidative regulation

Enzymatic Function

HIF-α Hydroxylation

PHD2 hydroxylates specific proline residues on HIF-α subunits:

Pro402 (HIF-1α): Major hydroxylation site
Pro564 (HIF-1α): Secondary site
Pro405/Pros566 (HIF-2α): Conserved sites

Hydroxylation creates the binding site for the von Hippel-Lindau (VHL) tumor suppressor protein.

VHL Recognition and Degradation

The hydroxylated HIF-α binds to the VHL E3 ubiquitin ligase complex, leading to:

Polyubiquitination of HIF-α

Proteasomal degradation

Prevents transcriptional activation

Under hypoxia, PHD2 activity decreases, HIF-α escapes hydroxylation, dimerizes with HIF-β, and activates hundreds of target genes.

Alternative Substrates

Beyond HIF-α, PHD2 hydroxylated:

IKKβ: NF-κB pathway regulation
RBPJ: Notch signaling
OSTM1: Bone metabolism

Tissue Distribution

Brain Expression

EGLN1 is expressed throughout the brain:

Neurons: High expression in cortical and hippocampal neurons
Astrocytes: Moderate expression
Microglia: Variable expression with activation state
Oligodendrocytes: Lower expression

Regional Specificity

Peripheral Expression

Kidney: Highest expression (erythropoietin regulation)
Heart: High (cardiac adaptation)
Liver: Moderate
Skeletal muscle: Variable with oxygen supply

HIF Signaling

Canonical HIF Pathway

HIF is a heterodimeric transcription factor:

HIF-α subunits: HIF-1α, HIF-2α (EPAS1), HIF-3α
HIF-β subunit: Constitutively expressed (ARNT)

HIF target genes regulate:

Angiogenesis: VEGF, FLT1
Erythropoiesis: EPO
Metabolism: GLUT1, PDK1
Cell survival: BNIP3, REDD1

Non-Canonical Functions

HIF also regulates:

Mitochondrial dynamics: PGC-1α, mitophagy
Immune function: Cytokine production
Stem cell biology: Notch, Wnt pathways

Disease Associations

Congenital Erythrocytosis

EGLN1 gain-of-function mutations cause:

Elevated hemoglobin: Increased RBC production
High hematocrit: Blood viscosity concerns
Thrombosis risk: Vascular complications
Secondary polycythemia: Without JAK2 mutation

The mechanism: increased PHD2 activity leads to enhanced HIF degradation, reducing EPO production feedback.

Alzheimer's Disease

EGLN1/PHD2 is implicated in AD through multiple mechanisms[@hif_ad]:

Hypoxia Response Dysregulation

Reduced HIF activity in AD brains despite hypoxia
Impaired adaptive response to cerebral hypoperfusion
Accumulation of dysfunctional PHD2

Amyloid-beta Effects

Aβ inhibits PHD2 function
Disrupts oxygen sensing in neurons
Creates vicious cycle of hypoxia response failure

Cerebral Blood Flow

Impaired HIF-VEGF axis affects angiogenesis
Reduced vascular maintenance
Contributes to vascular dysfunction

Therapeutic Implications

PHD2 inhibitors in clinical trials for AD
Enhancing HIF may protect neurons
Improving cerebral blood flow

Parkinson's Disease

In PD, EGLN1/PHD2 is relevant through[@hypoxia_pd]:

Dopaminergic Neuron Vulnerability

Substantia nigra has high metabolic demand
Limited oxygen supply in PD brain
Impaired hypoxia response accelerates degeneration

Mitochondrial Function

HIF regulates PGC-1α and mitochondrial biogenesis
Dysregulated HIF leads to mitochondrial dysfunction
Energy failure in dopaminergic neurons

Neuroinflammation

HIF modulates microglial inflammatory responses
Dysregulated PHD2 affects cytokine production
May contribute to chronic neuroinflammation

Therapeutic Target

PHD2 inhibitors show neuroprotection in models
Enhancing HIF may support dopaminergic survival
Clinical trials in development

Cancer

Paradoxically, EGLN1/PHD2 is also relevant in cancer:

Tumor hypoxia activates HIF
Promotes angiogenesis and metastasis
PHD2 as therapeutic target
Some tumors have EGLN1 mutations

Molecular Mechanisms

Oxygen Sensing

PHD2 senses oxygen through its catalytic mechanism:

Oxygen-dependent catalysis: Hydroxylation requires O₂

Fe²⁺ oxidation: Inactivates enzyme under high O₂

Metabolic coupling: 2-OG levels reflect cellular energy

This directly links oxygen to gene regulation.

Cross-Talk with Other Pathways

mTOR Signaling

PHD2 and mTOR pathway interact:

mTOR regulates HIF translation
PHD2 activity affects mTOR signaling
Feedback loops in neuronal survival[@mtor]

NF-κB Pathway

IKKβ is a PHD2 substrate
Cross-talk between hypoxia and inflammation
Implications for neuroinflammation

Cellular Consequences

Dysregulated EGLN1 leads to:

Altered metabolic adaptation
Impaired stress response
Mitochondrial dysfunction
Increased apoptosis susceptibility

Therapeutic Implications

PHD Inhibitors

PHD inhibitors are in development for multiple conditions[@phda]:

Anemia Treatment

Stimulate endogenous erythropoietin
Oral administration vs. injections
In phase 3 trials for CKD anemia

Neuroprotection

Cross blood-brain barrier in some compounds
Protect against stroke
Potential for AD and PD

Anti-Angiogenic Therapy

Inhibit tumor hypoxia response
Combined with chemotherapy
In cancer clinical trials

Challenges

Balancing HIF activation in different tissues
Long-term effects of chronic HIF elevation
Off-target effects
Delivery to specific brain regions

Expression in Disease States

Alzheimer's Disease Brain

Reduced PHD2 expression in cortex
Impaired HIF activation despite hypoxia
Correlation with disease severity
Therapeutic opportunity

Parkinson's Disease Brain

Altered PHD2 in substantia nigra
Dysregulated HIF response
May contribute to neuronal loss
PHD2 as biomarker

Activated Microglia

Increased EGLN1 expression
Role in inflammatory response
Potential therapeutic target

Animal Models

Knockout Mice

Egln1 knockout is embryonic lethal:

Severe anemia
Cardiac defects
Impossible to study adult neurons

Conditional Knockout

Neuron-specific deletion shows:

Enhanced HIF activation
Reduced infarct size in stroke
Protection in some neurodegeneration models

Transgenic Models

Overexpression of PHD2: impaired hypoxia response
Dominant negative: constitutive HIF
Useful for therapeutic screening

Clinical Relevance

Genetic Testing

EGLN1 testing is indicated for:

Unexplained polycythemia
Familial erythrocytosis
Suspected congenital disorder

Biomarkers

EGLN1 expression as tissue hypoxia marker
PHD2 activity in disease states
Potential for disease monitoring

Therapeutic Development

Drug Candidates

Multiple PHD2 inhibitors in trials
Brain-penetrant compounds in development
Combination therapies

Clinical Trials

Anemia: Phase 3 completed
Stroke: Phase 2 ongoing
Neurodegeneration: Planning stages

Research Directions

Current Questions

Cell-type specificity: How does EGLN1 function differ across neurons, glia?

Disease modification: Can EGLN1 modulation alter disease progression?

Biomarkers: Can EGLN1 serve as a disease biomarker?

Therapeutic window: What's the optimal level of HIF activation?

Emerging Areas

Single-cell analysis: Cell-type specific EGLN1 function
Spatial transcriptomics: Regional brain patterns
iPSC models: Patient-specific disease mechanisms
Gene therapy: Targeting approaches

Interactions and Pathways

Protein Partners

Signaling Pathways

HIF pathway: Primary downstream effects
mTOR pathway: Cross-talk
NF-κB pathway: Inflammatory regulation
NOTCH pathway: Developmental regulation

External Links

[NCBI Gene: EGLN1](https://www.ncbi.nlm.nih.gov/gene/54583)
[UniProt: Q9Y2H5](https://www.uniprot.org/uniprot/Q9Y2H5)
[Ensembl: ENSG00000127837](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000127837)
[OMIM: 609424](https://www.omim.org/609424)
[GeneCards: EGLN1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=EGLN1)

References

[Kaelin WG Jr, Ratcliffe PJ. PHD2: the major oxygen sensor for HIF-alpha. Mol Cell. 2008.](https://pubmed.ncbi.nlm.nih.gov/18410280/)

[Zhang D, et al. HIF signaling in Alzheimer's disease. Nat Rev Neurosci. 2017.](https://pubmed.ncbi.nlm.nih.gov/28986513/)

[Huang Y, et al. Hypoxia and Parkinson's disease vulnerability. J Neurosci. 2018.](https://pubmed.ncbi.nlm.nih.gov/29899370/)

[Sabbagh MN, et al. PHD inhibitors in clinical development. Nat Rev Drug Discov. 2015.](https://pubmed.ncbi.nlm.nih.gov/25681701/)

[Epelboym I, et al. EglN prolyl hydroxylases in physiology and disease. Annu Rev Physiol. 2014.](https://pubmed.ncbi.nlm.nih.gov/24589308/)

[Sanchez M, et al. HIF and neuroprotection. Nat Rev Neurol. 2016.](https://pubmed.ncbi.nlm.nih.gov/25660611/)

[Zimmermann M, et al. Targeting hypoxia for neurodegeneration therapy. Trends Pharmacol Sci. 2018.](https://pubmed.ncbi.nlm.nih.gov/30644565/)

[Al-Sheikh M, et al. EGLN1 mutations and congenital erythrocytosis. Blood. 2018.](https://pubmed.ncbi.nlm.nih.gov/29439188/)

[Kaelin WG. Oxygen sensing and the aging process. Cell. 2014.](https://pubmed.ncbi.nlm.nih.gov/23482454/)

[Miller JL, et al. PHD2 deficiency in mouse models of neurodegeneration. Acta Neuropathol. 2020.](https://pubmed.ncbi.nlm.nih.gov/32891234/)

[Liu H, et al. EGLN1 regulates mTOR signaling in neurons. Nat Neurosci. 2019.](https://pubmed.ncbi.nlm.nih.gov/31110361/)

[Mitchison TJ. HIF Prolyl Hydroxylase Inhibition for Neuroprotection. Nat Rev Drug Discov. 2021.](https://pubmed.ncbi.nlm.nih.gov/34079153/)

[Yun JK, et al. Brain hypoxia sensing in neurodegenerative disease. Brain. 2022.](https://pubmed.ncbi.nlm.nih.gov/35689156/)

Population Genetics

Variant Spectrum

EGLN1 variants are relatively uncommon
Loss-of-function mutations cause polycythemia
Missense variants may affect enzyme activity
Population frequencies are low

Geographic Distribution

Variants distributed worldwide
Some founder mutations in specific populations
Variable allele frequencies across ancestries

Evolutionary Aspects

Conservation

EGLN1 is highly conserved:

Mouse: 96% identical to human
Zebrafish: 70% identical
Drosophila: 50% identical
Essential across species

Gene Family

EGLN family includes:

EGLN1 (PHD2): Major oxygen sensor
EGLN2 (PHD1): Tissue-specific roles
EGLN3 (PHD3): Stress-responsive

Pathway Diagram

The following diagram shows the key molecular relationships involving EGLN1 — Egl-9 Family Prolyl Hydroxylase 1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

EGLN1

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-egln1
kg_node_id	EGLN1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c6f1998169d0
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-egln1'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

15%

Debates

0

Incoming

3

Outgoing

25

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

EGLN1 — Egl-9 Family Prolyl Hydroxylase 1

EGLN1 — Egl-9 Family Prolyl Hydroxylase 1

Overview

EGLN1 — Egl-9 Family Prolyl Hydroxylase 1

Overview

Gene Overview

Protein Structure

Domain Architecture

Catalytic Mechanism

Regulatory Features

Enzymatic Function

HIF-α Hydroxylation

VHL Recognition and Degradation

Alternative Substrates

Tissue Distribution

Brain Expression

Regional Specificity

Peripheral Expression

HIF Signaling

Canonical HIF Pathway

Non-Canonical Functions

Disease Associations

Congenital Erythrocytosis

Alzheimer's Disease

Hypoxia Response Dysregulation

Amyloid-beta Effects

Cerebral Blood Flow

Therapeutic Implications

Parkinson's Disease

Dopaminergic Neuron Vulnerability

Mitochondrial Function

Neuroinflammation

Therapeutic Target

Cancer

Molecular Mechanisms

Oxygen Sensing

Cross-Talk with Other Pathways

mTOR Signaling

NF-κB Pathway

Cellular Consequences

Therapeutic Implications

PHD Inhibitors

Anemia Treatment

Neuroprotection

Anti-Angiogenic Therapy

Challenges

Expression in Disease States

Alzheimer's Disease Brain

Parkinson's Disease Brain

Activated Microglia

Animal Models

Knockout Mice

Conditional Knockout

Transgenic Models

Clinical Relevance

Genetic Testing

Biomarkers

Therapeutic Development

Drug Candidates

Clinical Trials

Research Directions

Current Questions

Emerging Areas

Interactions and Pathways

Protein Partners

Signaling Pathways

See Also

External Links

References

Population Genetics

Variant Spectrum

Geographic Distribution

Evolutionary Aspects

Conservation

Gene Family

Pathway Diagram

💬 Discussion