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 page.
| Attribute | Value |
|---|---|
| Symbol | ANG |
| Gene Name | Angiogenin |
| Alias | RNASE5, Ribonuclease A Family Member 5 |
| Chromosome | 14q11.2 |
| Base Pair Position | 20,695,847-20,713,428 (GRCh38) |
| OMIM | 105400 |
| Ensembl | ENSG00000100939 |
| UniProt | P03950 |
| Protein Type | Secreted ribonuclease |
| Length | 147 amino acids |
| Expression | Broad, high in liver, brain, and motor neurons |
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.
ANG performs multiple functions critical to neuronal survival:
Ribonucleolytic Activity: ANG cleaves tRNA, rRNA precursors, and other RNA species. This activity is essential for:
Angiogenesis: Promotes blood vessel formation through:
Neuroprotection: ANG provides critical survival functions for motor neurons:
Stress Response: Under cellular stress, ANG:
Over 20 pathogenic mutations in ANG have been identified in ALS9 patients [1]. These mutations are distributed throughout the gene and affect different protein functions:
| Mutation | Location | Effect |
|---|---|---|
| K17I | Signal peptide | Loss of secretion |
| C39G | RNase domain | Disrupts protein folding |
| K40I | RNase domain | Impairs angiogenic function |
| R31H | RNase domain | Reduces neuroprotective capacity |
| P109L | RNase domain | Decreases ribonuclease activity |
| H48R | RNase domain | Alters substrate binding |
Mutations in ANG lead to ALS through several interconnected mechanisms [2]:
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 Stress Granule Dynamics: Stress granules are membrane-less organelles that form under cellular stress [3]. ANG mutations alter stress granule formation and clearance:
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. ANG mutations may synergize with TDP-43 dysregulation.
ANG mutations share pathways with other ALS genes:
ALS9 presents with typical ALS phenotype but with some distinctive features:
The disease typically manifests as:
ALS9 shows phenotypic variability:
Research on ANG as a biomarker:
ALS9 must be distinguished from:
Recombinant ANG Protein: Delivery of functional ANG protein to protect motor neurons. Preclinical studies showed efficacy in ALS models [4].
Gene Therapy: Viral vector delivery of wild-type ANG:
Small Molecule Activators: Compounds that enhance endogenous ANG activity:
RNA Metabolism Modulators: Address RNA processing defects:
ANG-targeted therapies have advanced to clinical trials:
Given the complexity of ALS pathogenesis:
Several ANG-ALS9 models have been developed:
These models demonstrate motor neuron dysfunction and validate ANG's pathogenic role.
Chen et al. ANG mutations in familial ALS (2007). 2007. ↩︎
Padua et al. ANG mutations and RNA metabolism in ALS. 2020. ↩︎
Watowich et al. ANG and stress granule formation in ALS. 2021. ↩︎
Bosch et al. ANG therapy in preclinical ALS models. 2019. ↩︎
Sweeney et al. ANG in ALS clinical trials. 2022. ↩︎