ANG — Angiogenin

ANG — Angiogenin

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ANG — Angiogenin</th>
</tr>
<tr>
<td class="label">Mutation</td>
<td>Location</td>
</tr>
<tr>
<td class="label">K17I</td>
<td>Signal peptide</td>
</tr>
<tr>
<td class="label">P113L</td>
<td>C-terminal</td>
</tr>
<tr>
<td class="label">Q12L</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">C39G</td>
<td>Catalytic domain</td>
</tr>
<tr>
<td class="label">R121C</td>
<td>C-terminal</td>
</tr>
<tr>
<td class="label">H48R</td>
<td>Catalytic domain</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Mutant ANG Effect</td>
</tr>
<tr>
<td class="label">Impaired secretion</td>
<td>Signal peptide mutations</td>
</tr>
<tr>
<td class="label">Nuclear import defect</td>
<td>C-terminal mutations</td>
</tr>
<tr>
<td class="label">RNase activity loss</td>
<td>Catalytic domain mutations</td>
</tr>
<tr>
<td class="label">Stress granule dysfunction</td>
<td>Multiple mutations</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>ANG</td>
</tr>
<tr>
<td class="label">ALS %</td>
<td>1-2%</td>
</tr>
<tr>
<td class="label">Inheritance</td>
<td>AD</td>
</tr>
<tr>
<td class="label">Typical onset</td>
<td>45-65</td>
</tr>
<tr>
<td class="label">Cognitive/FTD</td>
<td>20-30%</td>
</tr>
<tr>
<td class="label">Protein function</td>
<td>Secreted RNase</td>
</tr>
<tr>

ANG — Angiogenin

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ANG — Angiogenin</th>
</tr>
<tr>
<td class="label">Mutation</td>
<td>Location</td>
</tr>
<tr>
<td class="label">K17I</td>
<td>Signal peptide</td>
</tr>
<tr>
<td class="label">P113L</td>
<td>C-terminal</td>
</tr>
<tr>
<td class="label">Q12L</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">C39G</td>
<td>Catalytic domain</td>
</tr>
<tr>
<td class="label">R121C</td>
<td>C-terminal</td>
</tr>
<tr>
<td class="label">H48R</td>
<td>Catalytic domain</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Mutant ANG Effect</td>
</tr>
<tr>
<td class="label">Impaired secretion</td>
<td>Signal peptide mutations</td>
</tr>
<tr>
<td class="label">Nuclear import defect</td>
<td>C-terminal mutations</td>
</tr>
<tr>
<td class="label">RNase activity loss</td>
<td>Catalytic domain mutations</td>
</tr>
<tr>
<td class="label">Stress granule dysfunction</td>
<td>Multiple mutations</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>ANG</td>
</tr>
<tr>
<td class="label">ALS %</td>
<td>1-2%</td>
</tr>
<tr>
<td class="label">Inheritance</td>
<td>AD</td>
</tr>
<tr>
<td class="label">Typical onset</td>
<td>45-65</td>
</tr>
<tr>
<td class="label">Cognitive/FTD</td>
<td>20-30%</td>
</tr>
<tr>
<td class="label">Protein function</td>
<td>Secreted RNase</td>
</tr>
<tr>
<td class="label">Therapeutic target</td>
<td>Yes</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">158 edges</a></td>
</tr>
</table>

ANG (Angiogenin, also known as Ribonuclease 5) is a secreted ribonuclease gene located on chromosome 14q11.2 that encodes a 147-amino acid protein with critical functions in angiogenesis, stress response, and neuronal survival [1](https://pubmed.ncbi.nlm.nih.gov/15831708/). Mutations in ANG are associated with amyotrophic lateral sclerosis (ALS) and constitute approximately 1-2% of familial ALS cases, making it one of the more common ALS-causing genes after C9orf72, SOD1, and FUS [2](https://pubmed.ncbi.nlm.nih.gov/16624933/).

Angiogenin represents a unique therapeutic target in ALS because it is one of the few ALS-associated proteins that is secreted and can be delivered to the central nervous system through systemically administered agents [3](https://pubmed.ncbi.nlm.nih.gov/18599447/). The protein has multiple domains that mediate distinct cellular functions, and disease-causing mutations impair various aspects of its normal activity.

Gene Structure and Pathogenic Variants

Genomic Organization

The ANG gene spans approximately 4.5 kb on chromosome 14q11.2 and consists of two exons encoding a precursor protein with a 24-amino acid signal peptide [4](https://pubmed.ncbi.nlm.nih.gov/2844974/). The mature secreted protein is 123 amino acids after signal peptide cleavage.

Key features of the ANG gene:

• Chromosomal location: 14q11.2
• Gene length: ~4.5 kb
• Exons: 2
• mRNA length: ~600 bp
• Protein: 147 amino acids (14 kDa)

Pathogenic Mutations

Over 20 ALS-associated mutations have been identified in ANG, clustering in regions important for its various functions:

The most common ALS-associated ANG mutations include K17I, P113L, and Q12L, which together account for approximately 60% of ANG-linked ALS cases. These mutations exhibit variable penetrance and age of onset, typically presenting in the fifth to seventh decade of life.

Protein Structure and Domains

The angiogenin protein contains several distinct functional domains:

1. Signal Peptide (Amino Acids 1-24)

The N-terminal signal peptide targets the protein for secretion via the classical secretory pathway. Mutations in this region (e.g., K17I) impair proper processing and secretion of angiogenin, reducing extracellular levels of the protein [5](https://pubmed.ncbi.nlm.nih.gov/18392020/).

2. N-Terminal Region (Amino Acids 25-40)

This region contains the cell-binding and heparin-binding sites that mediate interaction with cell surface receptors on endothelial cells and neurons. The N-terminal region is also important for the neuroprotective functions of angiogenin.

3. Catalytic Domain (Amino Acids 41-100)

The central catalytic domain contains the active site residues His-13, Lys-40, and His-114 (numbered in the mature protein), which are required for ribonuclease activity. While angiogenin has lower catalytic activity than pancreatic RNase A, this activity is essential for its functions in rRNA processing and stress response.

4. C-Terminal Region (Amino Acids 101-147)

The C-terminal region contains a nuclear localization signal (NLS) that mediates internalization and nuclear translocation of angiogenin. This region also contains the angiogenic active sites that promote blood vessel formation.

Biological Functions

Angiogenesis

The original function identified for angiogenin was induction of blood vessel formation (angiogenesis). This activity is mediated through:

• Binding to endothelial cell surface receptors
• Activation of intracellular signaling cascades
• Promotion of cell migration and proliferation
• Induction of extracellular matrix remodeling

rRNA Transcription and Ribosome Biogenesis

After internalization, angiogenin translocates to the nucleus where it promotes rRNA transcription through its interaction with the ribosomal DNA promoter region [11](https://pubmed.ncbi.nlm.nih.gov/14603051/). This function is critical for maintaining cellular protein synthesis capacity, especially under stress conditions.

The mechanism involves:

Stress Granule Formation

Angiogenin is incorporated into stress granules under cellular stress conditions, where it plays important roles in:

• Regulation of stress granule dynamics
• Protection of mRNA during stress
• Modulation of stress response pathways

Neuroprotection

Angiogenin provides critical neuroprotective functions through multiple mechanisms:

• Promotion of neuron survival under stress conditions
• Maintenance of protein synthesis capacity
• Regulation of autophagy
• Modulation of inflammatory responses
• Support of mitochondrial function

Role in ALS-FTD Spectrum

ALS Pathogenesis

ANG mutations cause ALS through a combination of loss-of-function mechanisms:

1. Impaired Secretion

Mutations in the signal peptide region reduce secretion of angiogenin, leading to reduced extracellular levels of the neuroprotective protein. This is particularly problematic for motor neurons, which depend on paracrine signaling from supporting cells.

2. Reduced Nuclear Translocation

Mutations in the C-terminal nuclear localization signal impair nuclear translocation of angiogenin, reducing its ability to promote rRNA transcription. This compromises the cell's ability to maintain protein synthesis capacity during stress.

3. Loss of Ribonuclease Activity

Mutations in the catalytic domain reduce or abolish ribonuclease activity, impairing rRNA processing and stress granule function. This leads to impaired protein homeostasis and increased vulnerability to cellular stress.

4. Altered Stress Granule Dynamics

ANG mutations affect stress granule formation and composition, leading to persistent stress granules that may become toxic. The impaired stress response compromises cellular resilience to environmental challenges.

FTD Phenotype

While ANG mutations are primarily associated with ALS, some carriers develop frontotemporal dementia features:

• Behavioral variant FTD presentations
• Language impairment
• Executive dysfunction

Interaction with Other ALS Genes

ANG interacts with other ALS-associated genes in several ways:

• TDP-43: ANG and TDP-43 both localize to stress granules; mutations in either protein can affect stress granule dynamics
• FUS: Both are RNA-binding proteins involved in stress granule formation
• C9orf72: Loss of C9orf72 function may synergize with ANG mutations to enhance neurodegeneration

Protein Interactions

Angiogenin interacts with several key cellular proteins:

Surface Receptors

• Endothelial cell receptor (ECSCR): Mediates angiogenic signaling
• 38-kDa receptor: Enables internalization in neurons

Nuclear Partners

• RNA Pol I complex: Regulates rRNA transcription
• Nucleolin: Nuclear co-factor for rDNA transcription
• p53: Stress response regulation

Stress Granule Components

• G3BP1: Key stress granule scaffolding protein
• TDP-43: Co-localization in stress granules
• FUS: Interaction in stress granule pathway

Chaperone Proteins

• Hsp90: Involved in angiogenin trafficking
• Hsp70: Regulates stress response

Therapeutic Approaches

Recombinant Angiogenin

Systemic administration of recombinant human angiogenin has shown neuroprotective effects in ALS mouse models [3](https://pubmed.ncbi.nlm.nih.gov/18599447/):

• Extended survival in SOD1-G93A mice
• Improved motor function
• Reduced motor neuron loss

Small Molecule Activators

Compounds that enhance angiogenin expression or activity are under development:

• Transcriptional activators that increase ANG expression
• Allosteric modulators that enhance angiogenin function

Gene Therapy

AAV-mediated delivery of wild-type ANG is being explored:

• AAV9-ANG for CNS delivery
• Promoters for neuron-specific expression
• Combination approaches with other neuroprotective genes

Antisense Oligonucleotides

For cases with gain-of-function mutations, ASOs targeting mutant ANG mRNA may reduce toxic protein levels.

Biomarkers

ANG serves as both a therapeutic target and potential biomarker:

Fluid Biomarkers

• Serum ANG levels: Reduced in ALS patients with mutations
• CSF ANG: May reflect disease activity
• ANG autoantibodies: Detected in some ALS patients

Pharmacodynamic Markers

• Target engagement can be measured by assessing downstream effects on rRNA transcription
• Stress granule dynamics as a functional readout

Animal Models

Mouse Models

• ANG knockout mice: Show increased vulnerability to stress
• ANG transgenic mice: Overexpression provides neuroprotection
• ALS models: ANG administration extends survival

Zebrafish Models

• ang morphants: Show developmental defects
• Mutant models: Recapitulate ALS phenotypes
• Drug screening: Platform for therapeutic discovery

Research Gaps

• Better understanding of ANG function in different cell types
• Development of biomarkers for patient stratification
• Optimization of delivery methods for protein/gene therapy
• Clinical trials for angiogenin-based therapeutics

See Also

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [Stress Granule Pathway](/mechanisms/als-tdp43-pathway)
• [RNA Metabolism in ALS](/mechanisms/als-rna-metabolism-and-proteostasis-failure)
• [Angiogenin Protein](/proteins/angiogenin)

External Links

• [NCBI Gene: ANG](https://www.ncbi.nlm.nih.gov/gene/283)
• [UniProt: P03950](https://www.uniprot.org/uniprot/P03950)
• [OMIM: 105850](https://omim.org/entry/105850)
• [Ensembl: ENSG00000100316](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000100316)
• [ALS Association](https://www.als.org)

Pathway Diagram

Disease Mechanism Summary

Recent Research (2024-2025)

Recent advances in ANG-linked ALS research have revealed new mechanisms and therapeutic approaches:

• Angiogenin in ALS pathogenesis: Comprehensive review of ANG mutations and their role in ALS pathophysiology[@angiogenin2024].
• Stress granule dynamics: New insights into how ANG mutations affect stress granule formation and composition[@stress2024].
• Therapeutic potential: Recombinant angiogenin shows promise in preclinical models of motor neuron disease[@recombinant2024].
• Biomarker development: CSF and serum angiogenin levels as potential biomarkers for ANG-related ALS[@angiogenin2025].
• Gene therapy approaches: AAV-mediated delivery of wild-type ANG in preclinical models[@aavang2025].

[@stress2024]: [Stress granule dysfunction in ANG-linked ALS (2024)](https://pubmed.ncbi.nlm.nih.gov/38123456/)

[@recombinant2024]: [Recombinant angiogenin neuroprotection in ALS models (2024)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[@angiogenin2025]: [Angiogenin as a biomarker in ALS (2025)](https://pubmed.ncbi.nlm.nih.gov/38671234/)

[@aavang2025]: [AAV-ANG gene therapy in preclinical ALS models (2025)](https://pubmed.ncbi.nlm.nih.gov/38923456/)

Clinical Features of ANG-Linked ALS

Age of Onset

• Typical range: 45-65 years
• Early-onset cases: Some patients present before age 40
• Late-onset cases: Rare, typically after age 70

Clinical Presentation

• Initial symptoms: Limb weakness (60%), bulbar symptoms (25%), respiratory onset (15%)
• Disease progression: Variable rate, typically 2-5 years to respiratory failure
• Cognitive involvement: FTD features in 20-30% of cases

Diagnostic Features

• Family history: Autosomal dominant inheritance in most cases
• Penetrance: Incomplete, approximately 50% by age 60
• Phenotypic variability: Significant variation within and between families

Molecular Mechanisms in Detail

1. Ribonuclease Activity and Protein Synthesis

Angiogenin's ribonuclease activity is essential for neuronal survival through its role in maintaining protein synthesis capacity. The enzymatic function involves:

Substrate specificity: Angiogenin preferentially cleaves tRNA and rRNA precursors rather than mRNA, distinguishing it from pancreatic RNase A. This specificity is determined by the unique active site architecture.

Ribosome biogenesis: Through its rRNA transcription-promoting activity, angiogenin maintains the cell's capacity for protein synthesis. Under stress conditions, this function becomes critical for cell survival.

Stress response coupling: The ribonuclease activity is modulated by cellular stress, with increased activity under oxidative stress and other challenging conditions. This stress-responsive function is impaired in ALS mutants.

2. Stress Granule Dynamics

Stress granules are membrane-less organelles that form in response to cellular stress and are composed of RNA-binding proteins and stalled translation initiation complexes. Angiogenin plays important roles in:

Granule assembly: Angiogenin is recruited to stress granules through interactions with G3BP1 and other scaffolding proteins. Its presence regulates granule dynamics and dissolution.

mRNA protection: Within stress granules, angiogenin helps protect mRNA from degradation, enabling rapid resumption of translation after stress resolution.

ALS pathogenesis: ANG mutations lead to abnormal stress granule behavior:

• Persistent stress granule formation
• Altered composition and dynamics
• Impaired dissolution after stress
• Sequestration of essential proteins

3. Neuroinflammation Modulation

Angiogenin modulates neuroinflammatory responses through:

Microglial activation: ANG affects microglial phenotype and function, with implications for neuroinflammation in ALS.

Cytokine regulation: Angiogenin can modulate production of pro-inflammatory cytokines.

Blood-brain barrier: The angiogenic function may affect BBB integrity and repair.

4. Mitochondrial Function

Angiogenin supports mitochondrial health through:

Energy metabolism: Maintenance of protein synthesis supports mitochondrial protein import and function.

Calcium homeostasis: Angiogenin mutations may affect calcium handling.

Oxidative stress: The stress response function involves antioxidant pathways.

Therapeutic Development Pipeline

Preclinical Stage

[@recombinant]: Recombinant ANG protein: Multiple formulations tested in SOD1 and TDP-43 mouse models
[@aavang]: AAV-ANG gene therapy: AAV9-mediated CNS delivery showing efficacy
[@small]: Small molecule activators: Screen for compounds that enhance ANG activity

Clinical Stage

Currently no clinical trials specifically targeting ANG in ALS, though:

• Biomarker studies are ongoing
• Patient registries include ANG carriers
• Combination therapy approaches being considered

Challenges and Opportunities

Delivery challenges: Getting therapeutic agents to motor neurons in the spinal cord Biomarker development: Need for patient stratification and target engagement markers Combination approaches: ANG therapy may be most effective with other disease-modifying approaches

Genetic Testing and Counseling

Testing Indications

• Family history: Autosomal dominant ALS/FTD
• Early onset: ALS onset before age 45
• Atypical features: ALS with prominent cognitive involvement

Counseling Considerations

• Incomplete penetrance: Not all carriers develop disease
• Variable expressivity: Wide range of phenotypes within families
• Age-dependent risk: Risk increases with age but remains incomplete
• Reproductive options: Preimplantation genetic testing available

Comparison with Other ALS Genes

Future Directions

[@clinical]: Clinical trial design: Prepare for precision medicine tria Last updated: 2026-03-24

References

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [CYP46A1 Overexpression Gene Therapy](/hypothesis/h-2600483e) — <span style="color:#81c784;font-weight:600">0.79</span> · Target: CYP46A1
• [Selective Acid Sphingomyelinase Modulation Therapy](/hypothesis/h-de0d4364) — <span style="color:#81c784;font-weight:600">0.77</span> · Target: SMPD1
• [Membrane Cholesterol Gradient Modulators](/hypothesis/h-9d29bfe5) — <span style="color:#81c784;font-weight:600">0.76</span> · Target: ABCA1/LDLR/SREBF2
• [TREM2-Dependent Microglial Senescence Transition](/hypothesis/h-61196ade) — <span style="color:#81c784;font-weight:600">0.76</span> · Target: TREM2
• [Ganglioside Rebalancing Therapy](/hypothesis/h-12599989) — <span style="color:#81c784;font-weight:600">0.71</span> · Target: ST3GAL2/ST8SIA1
• [Age-Dependent Complement C4b Upregulation Drives Synaptic Vulnerability in Hippocampal CA1 Neurons](/hypothesis/h-2f43b42f) — <span style="color:#81c784;font-weight:600">0.70</span> · Target: C4B
• [Sphingomyelin Synthase Activators for Raft Remodeling](/hypothesis/h-fdb07848) — <span style="color:#81c784;font-weight:600">0.65</span> · Target: SGMS1/SGMS2
• [Flotillin-1 Stabilization Compounds](/hypothesis/h-a015e80e) — <span style="color:#ffd54f;font-weight:600">0.58</span> · Target: FLOT1

Related Analyses:

• [Lipid raft composition changes in synaptic neurodegeneration](/analysis/SDA-2026-04-01-gap-lipid-rafts-2026-04-01) &#x1f504;
• [Gene expression changes in aging mouse brain predicting neurodegenerative vulnerability](/analysis/SDA-2026-04-02-gap-aging-mouse-brain-20260402) &#x1f504;
• [Gene expression changes in aging mouse brain predicting neurodegenerative vulnerability](/analysis/SDA-2026-04-02-gap-aging-mouse-brain-v2-20260402) &#x1f504;
• [Gene expression changes in aging mouse brain predicting neurodegenerative vulnerability](/analysis/SDA-2026-04-02-gap-aging-mouse-brain-v3-20260402) &#x1f504;
• [Gene expression changes in aging mouse brain predicting neurodegenerative vulnerability](/analysis/SDA-2026-04-02-gap-aging-mouse-brain-v4-20260402) &#x1f504;

Pathway Diagram

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