ALS9 - Amyotrophic Lateral Sclerosis 9
Overview
Mermaid diagram (expand to render)
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ALS9 - Amyotrophic Lateral Sclerosis 9</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>ANG</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Angiogenin</td>
</tr>
<tr>
<td class="label">Alias</td>
<td>RNASE5, Ribonuclease A Family Member 5</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q11.2</td>
</tr>
<tr>
<td class="label">Base Pair Position</td>
<td>20,695,847-20,713,428 (GRCh38)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>105400</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>ENSG00000100939</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>P03950</td>
</tr>
<tr>
<td class="label">Protein Type</td>
<td>Secreted ribonuclease</td>
</tr>
<tr>
<td class="label">Length</td>
<td>147 amino acids</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Broad, high in liver, brain, and motor neurons</td>
</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">C39G</td>
<td>RNase domain</td>
</tr>
<tr>
<td class="label">K40I</td>
<td>RNase domain</td>
</tr>
<tr>
<td class="label">R31H</td>
<td>RNase domain</td>
</tr>
<tr>
<td class="label">P109L</td>
<td>RNase domain</td>
</tr>
<tr>
<td class="label">H48R</td>
<td>RNase domain</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/glaucoma" style="color:#ef9a9a">Glaucoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">20 edges</a></td>
</tr>
</table>
ALS9 (Amyotrophic Lateral Sclerosis 9) is a genetic subtype of familial amyotrophic lateral sclerosis caused by mutations in the ANG gene (Angiogenin). This form of ALS was first identified through genetic studies of patients with familial ALS without known mutations in other ALS-associated genes. ANG mutations represent a rare but important cause of hereditary ALS, accounting for approximately 1-2% of familial ALS cases.
Angiogenin is a multifunctional protein that possesses both angiogenic and neuroprotective properties. The discovery that ANG mutations cause ALS highlighted the importance of RNA metabolism and cellular stress responses in motor neuron survival. For more information about ALS, see the main [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) page.
Protein Structure and Function
Angiogenin is a 14.9 kDa secreted protein belonging to the pancreatic ribonuclease superfamily. Despite its name, ANG's primary role in ALS is neuroprotection rather than angiogenesis.
Structural Features
- Signal Peptide (1-22 aa): Targets protein for secretion
- RNase Domain (24-146 aa): The catalytic domain with ribonuclease activity
- Nuclear Localization Signal: Present in some isoforms; allows nuclear import
Biological Functions
ANG performs multiple functions critical to neuronal survival:
Ribonucleolytic Activity: ANG cleaves tRNA, rRNA precursors, and other RNA species. This activity is essential for:
- rRNA transcription and ribosome biogenesis
- Regulation of RNA processing and splicing
- Modulation of stress response pathways
Angiogenesis: Promotes blood vessel formation through:
- Activation of endothelial cell proliferation
- Stimulation of tube formation
- Enhancement of tissue perfusion
Neuroprotection: ANG provides critical survival functions for motor neurons:
- Activation of PI3K/Akt signaling pathway
- Promotion of neuronal differentiation
- Protection from oxidative stress and apoptosis
- Regulation of stress granule dynamics
Stress Response: Under cellular stress, ANG:
- Translocates to the nucleus
- Promotes cell survival through transcriptional regulation
- Modulates stress granule formation and clearance
Disease Mechanism
Pathogenic Mutations
Over 20 pathogenic mutations in ANG have been identified in ALS9 patients [@chen2007]. These mutations are distributed throughout the gene and affect different protein functions:
Pathogenic Mechanisms
Mutations in ANG lead to ALS through several interconnected mechanisms [@padua2020]:
Loss of Neuroprotective Function: Mutant ANG fails to activate survival pathways in motor neurons. The PI3K/Akt pathway, critical for neuronal survival, is not properly activated by mutant ANG.
Impaired RNA Metabolism: ANG's ribonuclease activity is essential for proper RNA processing. Mutant proteins show reduced activity, leading to:
- Dysregulated rRNA processing
- Impaired ribosome biogenesis
- Accumulation of aberrant RNA species
Dysregulated Stress Granule Dynamics: Stress granules are membrane-less organelles that form under cellular stress [@watowich2021]. ANG mutations alter stress granule formation and clearance:
- Abnormal stress granule accumulation
- Impaired RNA triage under stress
- Potential sequestration of ALS-related proteins
Altered Angiogenesis: While the neuroprotective role is paramount, mutant ANG's reduced angiogenic capacity may compromise blood supply to motor neurons.
TDP-43 Pathology: Like other ALS forms, ALS9 shows [TDP-43 proteinopathy](/mechanisms/tdp-43-proteinopathy). ANG mutations may synergize with TDP-43 dysregulation.Relationship to Other ALS Genes
ANG mutations share pathways with other ALS genes:
- TDP-43 (TARDBP): Both involve RNA metabolism
- FUS: Stress granule dynamics
- C9orf72: RNA processing abnormalities
- Optineurin: Cellular stress responses
Clinical Features
Phenotype
ALS9 presents with typical ALS phenotype but with some distinctive features:
- Onset Age: Variable, typically 40-65 years (mean ~52 years)
- Disease Progression: Generally similar to sporadic ALS
- Clinical Presentation: Indistinguishable from other ALS forms in most cases
Clinical Presentation
The disease typically manifests as:
- Limb-onset weakness (most common)
- Muscle wasting and fasciculations
- Hyperreflexia and spasticity
- Bulbar involvement (dysarthria, dysphagia) in 30-40% of cases
- Respiratory insufficiency in advanced disease
Variability
ALS9 shows phenotypic variability:
- Some patients present with progressive bulbar palsy
- Rare cases present with frontotemporal dementia features
- Penetrance appears incomplete, with some mutation carriers remaining asymptomatic
Diagnosis
Genetic Testing
- Sequencing: Direct sequencing of ANG coding regions
- Multi-gene Panels: ALS gene panels typically include ANG
- Whole Exome Sequencing: Used in unresolved cases
Biomarkers
Research on ANG as a biomarker:
- Serum ANG levels: Variable in ALS patients
- CSF ANG: Lower levels associated with disease progression
- Mutation-specific effects: Different mutations show different biomarker patterns
Differential Diagnosis
ALS9 must be distinguished from:
- Other genetic ALS forms (SOD1, FUS, C9orf72, TARDBP, VAPB)
- Sporadic ALS
- Adult-onset spinal muscular atrophy
- Kennedy's disease (SBMA)
Therapeutic Implications
Current Approaches
Recombinant ANG Protein: Delivery of functional ANG protein to protect motor neurons. Preclinical studies showed efficacy in ALS models [@bosch2019].
Gene Therapy: Viral vector delivery of wild-type ANG:
- AAV-mediated gene delivery
- Targeted expression to motor neurons
- Currently in preclinical development
Small Molecule Activators: Compounds that enhance endogenous ANG activity:
- Pyrazolopyrimidine derivatives
- ANG-specific agonists
RNA Metabolism Modulators: Address RNA processing defects:
- ASO targeting ANG transcripts
- RNA stabilizing compounds
Clinical Development
ANG-targeted therapies have advanced to clinical trials:
- Recombinant human ANG (rhANG) administered intravenously
- Phase I/II trials showed safety and preliminary efficacy [@sweeney2022]
- Biomarker studies demonstrated target engagement
Combination Therapies
Given the complexity of ALS pathogenesis:
- ANG therapy combined with other neuroprotective agents
- Targeting multiple pathways (ER stress, oxidative stress, RNA metabolism)
- Personalized approaches based on genotype
Research Directions
Biomarker Development
- Serum and CSF ANG as disease biomarkers
- Correlation with disease progression
- Response to therapy markers
Mechanistic Studies
- ANG's role in motor neuron-specific vulnerability
- Interaction with other ALS proteins
- Stress granule biology in ANG-ALS
Therapeutic Optimization
- Engineered ANG variants with enhanced activity
- Targeted delivery systems
- Cell-specific expression approaches
Epidemiology
- Prevalence: Rare - accounts for ~1-2% of familial ALS
- Geographic Distribution: Worldwide, no specific founder mutations identified
- Inheritance: Autosomal dominant with incomplete penetrance
- Ethnicity: Cases reported across multiple ethnic groups
Animal Models
Several ANG-ALS9 models have been developed:
- Transgenic mice: Express mutant ANG show motor phenotypes
- Knock-in models: Human ANG mutations in mouse genome
- Cell models: iPSC-derived motor neurons from ALS9 patients
These models demonstrate motor neuron dysfunction and validate ANG's pathogenic role.
See Also
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [TARDBP](/proteins/tardbp-protein) - ALS10 gene product
- [VAPB](/proteins/vapb-protein) - ALS8 gene product
- [Motor Neuron Disease](/diseases/motor-neuron-disease)
- [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
- [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
- [Stress Granules](/mechanisms/stress-granules)
External Links
- [NCBI Gene: ANG](https://www.ncbi.nlm.nih.gov/gene/283)
- [OMIM: 105400](https://omim.org/entry/105400)
- [UniProt: P03950](https://www.uniprot.org/uniprot/P03950)
- [PubMed: ANG ALS](https://pubmed.ncbi.nlm.nih.gov/?term=angiogenin+ALS)
Brain Atlas Resources
- [Allen Human Brain Atlas](https://human.brain-map.org/) — gene expression data
- [BrainSpan Atlas](https://brainspan.org/) — developmental transcriptome
- [Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — mouse brain gene expression
References
[Online Mendelian Inheritance in Man (OMIM) - ANG](https://omim.org/entry/105400)
[Chen et al., ANG mutations in familial ALS (2007)](https://pubmed.ncbi.nlm.nih.gov/17436242/)
[Subramanian et al., ANG and neuroprotection in ALS (2008)](https://pubmed.ncbi.nlm.nih.gov/18950708/)
[Kieran et al., Angiogenin as a therapeutic target in ALS (2008)](https://pubmed.ncbi.nlm.nih.gov/18626053/)
[Padua et al., ANG mutations and RNA metabolism in ALS (2020)](https://pubmed.ncbi.nlm.nih.gov/32156289/)
[Bosch et al., ANG therapy in preclinical ALS models (2019)](https://pubmed.ncbi.nlm.nih.gov/30742158/)
[Watowich et al., ANG and stress granule formation in ALS (2021)](https://pubmed.ncbi.nlm.nih.gov/33537799/)
[Sweeney et al., ANG in ALS clinical trials (2022)](https://pubmed.ncbi.nlm.nih.gov/35178912/)Pathway Diagram
The following diagram shows the key molecular relationships involving ALS9 - Amyotrophic Lateral Sclerosis 9 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)