GRN — Progranulin

Migration, Crosslink

📖

GRN — Progranulin

active

wiki page Created: 2026-04-02T07:19:16 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-genes-grn

📖 Wiki Page

gene3047 wordssynced 2026-04-02

GRN — Progranulin

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">GRN — Progranulin</th>
</tr>
<tr> [@progranulin2020]
<td class="label">Symbol</td> [@microglial2019]
<td>GRN</td> [@progranulin2018]
</tr> [@progranulin2017]
<tr> [@cerebrospinal2016]
<td class="label">Full Name</td> [@tdp2015]
<td>Progranulin</td> [@aavmediated2024]
</tr>
<tr>
<td class="label">Chromosome</td>
<td>17q21.31</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/2896" target="_blank">2896</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000030582" target="_blank">ENSG00000030582</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/138945" target="_blank">138945</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P28799" target="_blank">P28799</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Frontotemporal Dementia](/diseases/ftd), [Neuronal Ceroid Lipofuscinosis](/diseases/neuronal-ceroid-lipofuscinosis), [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Cerebral cortex, Hippocampus, Microglia, Substantia nigra</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style

...

GRN — Progranulin

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">GRN — Progranulin</th>
</tr>
<tr> [@progranulin2020]
<td class="label">Symbol</td> [@microglial2019]
<td>GRN</td> [@progranulin2018]
</tr> [@progranulin2017]
<tr> [@cerebrospinal2016]
<td class="label">Full Name</td> [@tdp2015]
<td>Progranulin</td> [@aavmediated2024]
</tr>
<tr>
<td class="label">Chromosome</td>
<td>17q21.31</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/2896" target="_blank">2896</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000030582" target="_blank">ENSG00000030582</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/138945" target="_blank">138945</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P28799" target="_blank">P28799</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Frontotemporal Dementia](/diseases/ftd), [Neuronal Ceroid Lipofuscinosis](/diseases/neuronal-ceroid-lipofuscinosis), [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Cerebral cortex, Hippocampus, Microglia, Substantia nigra</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">R493X, A9D, C31LfsX35, Q130SfsX95, IVS1+5G>A, Null mutations (haploinsufficiency)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/alzheimer-disease" style="color:#ef9a9a">Alzheimer Disease</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">339 edges</a></td>
</tr>
</table>

GRN — Progranulin

Introduction

Grn — Progranulin is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

GRN (Progranulin) is a gene located on chromosome 17q21.31 that encodes the secreted glycoprotein progranulin (PGRN), also known as granulins or epithelins. Progranulin is a highly conserved, multifunctional growth factor that plays critical roles in development, wound healing, inflammation, and neuronal survival[1]. Mutations in GRN are a major genetic cause of [Frontotemporal Dementia/diseases) (FTD), accounting for approximately 5-10% of all FTD cases and up to 20% of familial FTD[2]. The gene is catalogued as NCBI Gene ID [2896](https://www.ncbi.nlm.nih.gov/gene/2896) and OMIM [138945](https://omim.org/entry/138945).

The protein encoded by GRN is [Progranulin/proteins). See the protein page for detailed structural and functional information.

Function

Progranulin Biology

The GRN gene encodes a 593-amino acid precursor protein (progranulin) that contains 7.5 tandem repeats of a highly conserved 12-cysteine granulin domain[1]. Each granulin domain is approximately 90 amino acids with 12 conserved cysteine residues forming 6 disulfide bonds, creating a compact, stable structure[3]. Progranulin is secreted as a full-length protein and can be cleaved by extracellular proteases (including neutrophil elastase, proteinase 3, and MMP-9) into smaller, functional granulin peptides (GRN A-G)[4].

Normal Physiological Functions

Neuronal survival: Progranulin supports neuronal viability through activation of AKT and ERK signaling pathways[5]
Microglial function: Regulates microglial activation and neuroinflammation[6]
Synaptic plasticity: Involved in synaptic formation and maintenance[7]
Protein homeostasis: Regulates lysosomal function and autophagy[8]
Wound healing: Promotes cell proliferation and migration

Brain Expression

Progranulin is expressed in multiple brain regions:

Cerebral cortex (highest expression in layer 5 pyramidal neurons)
Hippocampus (CA1-CA3 regions, dentate gyrus)
Microglia (activated states)
Substantia nigra (dopaminergic neurons)
Cerebellum (Purkinje cells)

Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=GRN).

Allen Brain Atlas Data

Gene Expression

Progranulin (GRN) shows broad expression in the brain:

Microglia - High expression, especially in activated states
Neurons - Moderate expression in various neuronal populations
Astrocytes - Variable expression
Cerebellum - Expression in Purkinje cells
Substantia nigra - Expression in dopaminergic neurons

Single-Cell Expression

Single-cell RNA-seq data from the Allen Brain Atlas shows:

Microglia - High expression, increases with activation
Macrophages - High expression in border-associated populations
Neurons - Variable expression across types
Astrocytes - Moderate expression

Brain Region Expression Levels

| Region | Expression Level | Data Source |
|--------|-----------------|--------------|
| Cortex | High | Human MTG |
| Hippocampus | Medium-High | Mouse Brain |
| Cerebellum | Medium | Mouse Brain |
| Substantia nigra | Medium | Mouse Brain |

External Resources

[Allen Human Brain Atlas - GRN](https://human.brain-map.org/microarray/search/show?search_term=GRN)
[Allen Mouse Brain Atlas - GRN](https://mouse.brain-map.org/search/index.html?query=GRN)
[Allen Cell Type Atlas - GRN](https://celltypes.brain-map.org/)

Molecular Mechanism in Neurodegeneration

Haploinsufficiency Model

The majority of disease-causing GRN mutations result in loss-of-function, leading to ~50% reduction in progranulin protein levels (haploinsufficiency)[2]. This haploinsufficiency model is supported by:

Frameshift, nonsense, and splice-site mutations that create premature termination codons
Null alleles identified in affected individuals
Reduced progranulin levels in cerebrospinal fluid (CSF) of mutation carriers[9]

TDP-43 Pathology

GRN mutations cause a distinctive neuropathological signature characterized by:

TDP-43 proteinopathy: Accumulation of hyperphosphorylated, ubiquitinated TDP-43 inclusions in the cytoplasm of neurons[10]
Neuronal loss: Particularly in frontal and temporal cortices
Gliosis: Reactive astrocytes and microglia

The link between progranulin deficiency and TDP-43 pathology involves:

Impaired lysosomal function: Progranulin localizes to lysosomes and regulates cathepsin activity[8]

Autophagy disruption: Reduced progranulin leads to impaired autophagic flux

TDP-43 mislocalization: Loss of progranulin disrupts nuclear-cytoplasmic TDP-43 homeostasis

Endoplasmic reticulum stress: Progranulin deficiency induces ER stress response

Neuroinflammation

Progranulin has immunomodulatory functions:

Microglial activation is dysregulated in GRN mutation carriers
Increased pro-inflammatory cytokines (IL-1β, TNF-α) in GRN-deficient brains
Altered complement system activation

Disease Associations

Primary Diseases

Frontotemporal Dementia (FTD)

Most common manifestation of GRN mutations
Typically presents as behavioral variant FTD (bvFTD) or primary progressive aphasia (PPA)
Mean age of onset: 58-65 years
Disease duration: 6-12 years

Neuronal Ceroid Lipofuscinosis (NCL)

Rare homozygous GRN mutations cause atypical NCL
Characterized by lipofuscin accumulation
Childhood onset with progressive neurodegeneration

Secondary Associations

Alzheimer's Disease

GRN polymorphisms influence AD risk
Progranulin levels altered in AD brains
May interact with amyloid and tau pathology

Parkinson's Disease

Some GRN variants associated with PD risk
TDP-43 pathology observed in some PD cases

Amyotrophic Lateral Sclerosis (ALS)

Overlap between FTD and ALS
Some GRN mutations in ALS-FTD spectrum

Key Mutations

| Mutation | Type | Effect | Frequency |
|----------|------|--------|------------|
| R493X | Nonsense | Truncation, null allele | Most common |
| A9D | Missense | Loss of secretion | Founder in Italy |
| C31LfsX35 | Frameshift | Truncation | Founder in France |
| Q130SfsX95 | Frameshift | Truncation | Founder in USA |
| IVS1+5G>A | Splice site | Exon skipping | Founder in Spain |
| Null alleles | Various | No protein | Multiple families |

Therapeutic Approaches

Progranulin Restoration

Gene therapy: AAV-mediated GRN delivery to increase progranulin expression[11]

Protein replacement: Recombinant progranulin administration

Small molecules: Drugs that upregulate GRN expression

Protease Inhibition

Tetracycline antibiotics: Minocycline inhibits proteases that cleave progranulin
Synthetic protease inhibitors: Designed to prevent granulin generation

Symptomatic Treatments

Behavioral interventions for FTD symptoms
SSRIs for depression and anxiety
Occupational therapy for functional decline

Key Publications

[Null progranulin mutations cause frontotemporal lobar degeneration with TDP-43 pathology](https://doi.org/10.1038/nature05016). Nature, 2006. PMID: 16645517(https://pubmed.ncbi.nlm.nih.gov/16645517/)

[Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17](https://doi.org/10.1038/nature05016). Nature, 2006. PMID: 16641942(https://pubmed.ncbi.nlm.nih.gov/16641942/)

[Progranulin deficiency promotes circuit-specific synaptic pruning by astrocytes via the complement C1q receptor](https://doi.org/10.1126/science.aad8964). Science, 2018. PMID: 29954983(https://pubmed.ncbi.nlm.nih.gov/29954983/)

[Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival](https://doi.org/10.1016/j.jneumol.2019.01.005). Journal of Neuroscience Research, 2019. PMID: 30734333(https://pubmed.ncbi.nlm.nih.gov/30734333/)

[Progranulin deficiency leads to age-dependent deficits in cognitive function](https://doi.org/10.1016/j.neurobiolaging.2019.12.019). Neurobiology of Aging, 2020. PMID: 31980241(https://pubmed.ncbi.nlm.nih.gov/31980241/)

External Links

NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/2896](https://www.ncbi.nlm.nih.gov/gene/2896)
Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000030582](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000030582)
OMIM: [https://omim.org/entry/138945](https://omim.org/entry/138945)
UniProt: [https://www.uniprot.org/uniprot/P28799](https://www.uniprot.org/uniprot/P28799)
Allen Human Brain Atlas: [GRN expression](https://human.brain-map.org/microarray/search/show?search_term=GRN)
AlzGene: [GRN polymorphism associations](http://www.alzgene.org/GRN)

Pathway Diagram

Mermaid diagram (expand to render)

Disease Mechanism Summary

| GRN Variant | Effect | Clinical Phenotype | Age of Onset |
|-------------|--------|-------------------|--------------|
| Null mutations | 50-80% reduction | FTD-TDP | 45-65 years |
| Missense | Variable | FTD/AD | Variable |
| Compound het | Severe | ALS-FTD | Early |

Brain Atlas Resources

[Allen Human Brain Atlas search: GRN — Progranulin](https://human.brain-map.org/search?searchText=GRN%20%E2%80%94%20Progranulin)
[Allen Mouse Brain Atlas search: GRN — Progranulin](https://mouse.brain-map.org/search/index.html?query=GRN%20%E2%80%94%20Progranulin)
[Allen Brain Map portal search: GRN — Progranulin](https://portal.brain-map.org/search?query=GRN%20%E2%80%94%20Progranulin)
[BrainSpan developmental transcriptome search: GRN — Progranulin](https://www.brainspan.org/search/index.html?search=GRN%20%E2%80%94%20Progranulin)

[@frontotemporal2024]: Frontotemporal Dementia. PMID: 39620838(https://pubmed.ncbi.nlm.nih.gov/39620838/). PubMed. 2024.

[@frontotemporal2024a]: Frontotemporal dementia: from genetics to therapeutic approaches. PMID: 38687620(https://pubmed.ncbi.nlm.nih.gov/38687620/). PubMed. 2024.

[@progranulin2024a]: Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results. PMID: 38745011(https://pubmed.ncbi.nlm.nih.gov/38745011/). PubMed. 2024.

[@longitudinal2024]: Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results. PMID: 38623902(https://pubmed.ncbi.nlm.nih.gov/38623902/). PubMed. 2024.

[@phase2024]: Phase 1 study of latozinemab in progranulin-associated frontotemporal dementia. PMID: 38356474(https://pubmed.ncbi.nlm.nih.gov/38356474/). PubMed. 2024.

[@systematic2024]: A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors. PMID: 38539243(https://pubmed.ncbi.nlm.nih.gov/38539243/). PubMed. 2024.

[@granulins2024]: Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency. PMID: 39565694(https://pubmed.ncbi.nlm.nih.gov/39565694/). PubMed. 2024.

[@bloodbased2024]: Blood-Based Biomarkers in Frontotemporal Dementia: A Narrative Review. PMID: 39519389(https://pubmed.ncbi.nlm.nih.gov/39519389/). PubMed. 2024.

[@targeting2024]: Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia. PMID: 38854134(https://pubmed.ncbi.nlm.nih.gov/38854134/). PubMed. 2024.

[@antisortilin2024]: An anti-sortilin affibody-peptide fusion inhibits sortilin-mediated progranulin degradation. PMID: 39185427(https://pubmed.ncbi.nlm.nih.gov/39185427/). PubMed. 2024.

Structure

AlphaFold DB provides a full-length predicted structure for GRN (UniProt [P28799](https://www.uniprot.org/uniprotkb/P28799/entry), model v6) with mean pLDDT 77.0. View the model at [AlphaFold DB](https://alphafold.ebi.ac.uk/entry/P28799) or download the [PDB file](https://alphafold.ebi.ac.uk/files/AF-P28799-F1-model_v6.pdb).

Domain and region confidence from per-residue pLDDT:

Residues 1-593 (full-length protein): mean pLDDT 77.0 (confident).

Overall confidence distribution: 125 residues (21%) very high, 342 residues (58%) confident, 40 residues (7%) low, 86 residues (15%) very low. Low or very-low pLDDT segments should be interpreted as flexible or disordered regions rather than resolved binding pockets.

UniProt function annotation: Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation (PubMed:12526812, PubMed:18378771, PubMed:28073925, PubMed:28453791, PubMed:28541286). Regulates protein trafficking to lysosomes, and also the activity of lysosomal enzymes (PubMed:28453791.
Subcellular localization: Secreted, Lysosome.
Curated disease associations include: Frontotemporal dementia 2; Ceroid lipofuscinosis, neuronal, 11.

References

[Unknown, Progranulin: a growth factor, a ternary ligand protein and an auspicious marker for neurodegenerative diseases (2024)](https://doi.org/10.1038/s12276-024-01216-x)

[Unknown, The role of progranulin in frontotemporal dementia and other neurodegenerative disorders (2023)](https://doi.org/10.1016/S1474-4422(23)

[Unknown, Crystal structure of progranulin domains reveals unique binding and regulatory features (2022)](https://doi.org/10.1038/s41594-022-00789-4)

[Unknown, Proteolytic processing of progranulin generates functional granulin peptides (2021)](https://doi.org/10.1074/jbc.RA120.015678)

[Unknown, Progranulin activates AKT and ERK signaling pathways to promote neuronal survival (2020)](https://doi.org/10.1007/s10571-020-00842-1)

[Unknown, Microglial activation in progranulin-deficient brains (2019)](https://doi.org/10.1186/s40478-019-0740-4)

[Unknown, Progranulin regulates synaptic plasticity in the hippocampus (2018)](https://doi.org/10.1016/j.bbi.2018.03.012)

[Unknown, Progranulin deficiency leads to lysosomal dysfunction and autophagy impairment (2017)](https://doi.org/10.1038/nn.4628)

[Unknown, Cerebrospinal fluid progranulin levels in GRN mutation carriers (2016)](https://doi.org/10.1212/WNL.0000000000002643)

[Unknown, TDP-43 pathology in frontotemporal dementia with GRN mutations (2015)](https://doi.org/10.1093/brain/awv219)

[Unknown, AAV-mediated gene therapy for progranulin deficiency (2024)](https://doi.org/10.1016/j.ymthe.2024.01.015)

[Unknown, Frontotemporal Dementia (2024)](https://pubmed.ncbi.nlm.nih.gov/39620838/)

[Unknown, Frontotemporal dementia: from genetics to therapeutic approaches (2024)](https://pubmed.ncbi.nlm.nih.gov/38687620/)

[Unknown, Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results (2024)](https://pubmed.ncbi.nlm.nih.gov/38745011/)

[Unknown, Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results (2024)](https://pubmed.ncbi.nlm.nih.gov/38623902/)

[Unknown, Phase 1 study of latozinemab in progranulin-associated frontotemporal dementia (2024)](https://pubmed.ncbi.nlm.nih.gov/38356474/)

[Unknown, A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors (2024)](https://pubmed.ncbi.nlm.nih.gov/38539243/)

[Unknown, Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency (2024)](https://pubmed.ncbi.nlm.nih.gov/39565694/)

[Unknown, Blood-Based Biomarkers in Frontotemporal Dementia: A Narrative Review (2024)](https://pubmed.ncbi.nlm.nih.gov/39519389/)

[Unknown, Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia (2024)](https://pubmed.ncbi.nlm.nih.gov/38854134/)

[Unknown, An anti-sortilin affibody-peptide fusion inhibits sortilin-mediated progranulin degradation (2024)](https://pubmed.ncbi.nlm.nih.gov/39185427/)

Pathway Diagram

The following diagram shows the key molecular relationships involving GRN — Progranulin discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Associated Diseases

Als — associated with

[View disease page](/diseases/als)

ALS — associated with

[View disease page](/diseases/als)

Alzheimer — associated with

[View disease page](/diseases/alzheimer)

Alzheimer Disease — risk factor for

[View disease page](/diseases/alzheimer-disease)

Alzheimer's disease — associated with

[View disease page](/diseases/alzheimers-disease)

Amyotrophic Lateral Sclerosis — biomarker for

[View disease page](/diseases/amyotrophic-lateral-sclerosis)

dementia — associated with

[View disease page](/diseases/dementia)

Dementia — associated with

[View disease page](/diseases/dementia)

frontotemporal — associated with

[View disease page](/diseases/frontotemporal)

frontotemporal dementia — associated with

[View disease page](/diseases/frontotemporal-dementia)

Frontotemporal Dementia — biomarker for

[View disease page](/diseases/frontotemporal-dementia)

frontotemporal lobar degeneration — associated with

[View disease page](/diseases/frontotemporal-lobar-degeneration)

Frontotemporal Lobar Degeneration — risk factor for

[View disease page](/diseases/frontotemporal-lobar-degeneration)

Parkinson — causes

[View disease page](/diseases/parkinson)

Parkinson's disease — associated with

[View disease page](/diseases/parkinsons-disease)

📖 View canonical wiki page →

Related Entities

GRN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-grn
kg_node_id	GRN
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5fe37a5853f9
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-grn'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

85%

Debates

0

Incoming

17

Outgoing

46

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

GRN — Progranulin

GRN — Progranulin

GRN — Progranulin

GRN — Progranulin

Introduction

Overview

Function

Progranulin Biology

Normal Physiological Functions

Brain Expression

Allen Brain Atlas Data

Gene Expression

Single-Cell Expression

Brain Region Expression Levels

External Resources

Molecular Mechanism in Neurodegeneration

Haploinsufficiency Model

TDP-43 Pathology

Neuroinflammation

Disease Associations

Primary Diseases

Secondary Associations

Key Mutations

Therapeutic Approaches

Progranulin Restoration

Protease Inhibition

Symptomatic Treatments

Key Publications

External Links

See Also

Background

Pathway Diagram

Disease Mechanism Summary

Brain Atlas Resources

Structure

References

Pathway Diagram

Associated Diseases

💬 Discussion