ALS9 - Amyotrophic Lateral Sclerosis 9

ALS9 - Amyotrophic Lateral Sclerosis 9

Overview

ALS9 - Amyotrophic Lateral Sclerosis 9

Overview

<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.

Gene Information

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:

• rRNA transcription and ribosome biogenesis
• Regulation of RNA processing and splicing
• Modulation of stress response pathways

• Activation of endothelial cell proliferation
• Stimulation of tube formation
• Enhancement of tissue perfusion

• Activation of PI3K/Akt signaling pathway
• Promotion of neuronal differentiation
• Protection from oxidative stress and apoptosis
• Regulation of stress granule dynamics

• 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]:

• Dysregulated rRNA processing
• Impaired ribosome biogenesis
• Accumulation of aberrant RNA species

• Abnormal stress granule accumulation
• Impaired RNA triage under stress
• Potential sequestration of ALS-related proteins

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

• AAV-mediated gene delivery
• Targeted expression to motor neurons
• Currently in preclinical development

• Pyrazolopyrimidine derivatives
• ANG-specific agonists

• 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

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

Pathway Diagram

The following diagram shows the key molecular relationships involving ALS9 - Amyotrophic Lateral Sclerosis 9 discovered through SciDEX knowledge graph analysis: