| ALS2 — Alsin | |
|---|---|
| Symbol | ALS2 |
| Full Name | Alsin |
| Chromosome | 2q33.1 |
| NCBI Gene | 617 |
| Ensembl | ENSG00000103337 |
| OMIM | 607352 |
| UniProt | Q9UPN3 |
| Protein Name | Alsin |
| Protein Length | 1,841 amino acids |
| Molecular Weight | 199 kDa |
| Brain Expression | High: motor cortex, spinal cord, basal ganglia |
| Subcellular Localization | Cytoplasm, Endosomes, Plasma membrane |
| Associated Diseases | Juvenile ALS, Primary Lateral Sclerosis, Infantile-Onset Ascending Hereditary Spastic Paraplegia |
Als2 Gene Alsin is a gene that has been implicated in neurodegenerative diseases. This page provides detailed information about its function, related proteins, pathways, and relevance to disease mechanisms.
ALS2 (Alsin) is a gene located on chromosome 2q33.1 that encodes a large Rab GTPase-activating protein (GAP) essential for neuronal survival and function[1]. The alsin protein (1,841 amino acids, ~199 kDa) contains multiple functional domains including RCC1-like domains (guanine nucleotide exchange factor-like), a VPS9 domain (which functions as a Rab5 GEF), and MORN (Membrane Occupation and Recognition Nexus) repeats[2].
Mutations in ALS2 cause a spectrum of autosomal recessive neurodegenerative disorders, including juvenile-onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis (PLS), and infantile-onset ascending hereditary spastic paralysis (IAHSP)[3][4]. These conditions are characterized by progressive upper motor neuron degeneration, leading to spasticity, weakness, and eventual paralysis.
The gene is catalogued as NCBI Gene ID 617 and OMIM 607352.
The ALS2 gene spans approximately 80 kb on chromosome 2q33.1 and contains 34 exons[1:1]. The gene encodes a single major protein isoform expressed predominantly in neural tissues.
Alsin contains several distinct functional domains:[2:1]
Alsin functions primarily as a dual-specificity Rab GTPase regulator:[2:2][5]
ALS2/Alsin → Rab5 activation → Early endosome fusion
→ Rab8 activation → Membrane trafficking
→ Rab11 activation → Recycling endosomes
ALS2 is highly expressed in the central nervous system:[1:2]
The selective expression in upper and lower motor neurons explains the motor neuron-specific phenotype in ALS2 disorders[3:1][4:1].
Within neurons, alsin localizes to:
Autosomal recessive mutations in ALS2 cause juvenile-onset ALS with onset between ages 3-20 years[3:2]:
Clinical Features:
Pathogenic Mutations:
| Mutation | Type | Effect |
|---|---|---|
| Q359X | Nonsense | Truncated protein, loss of function |
| L380fs | Frameshift | Premature termination |
| Exon 1 deletion | Genomic deletion | Complete loss of alsin |
Some ALS2 mutations cause a milder phenotype presenting in adolescence or early adulthood as PLS[4:2]:
The most severe ALS2 phenotype presents in infancy with:[4:3]
Loss of alsin function disrupts endosomal trafficking:[2:3][5:1]
Alsin deficiency impairs axonal vesicle trafficking:[6]
Alsin protects against mitochondrial oxidative stress:[7]
Alsin regulates signaling through:[8]
AAV-mediated delivery of wild-type ALS2 is being investigated:[9]
Recombinant alsin protein delivery faces challenges due to:
The study of Als2 Gene Alsin has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Hadano S, et al. (2001). Cloning and expression of ALS2. Nat Genet, 29(2), 166-173. ↩︎ ↩︎ ↩︎ ↩︎
Yang Y, et al. (2001). ALS2 mutations in juvenile ALS. Nature, 414(6859), 423-432. ↩︎ ↩︎ ↩︎
Gros-Louis F, et al. (2003). Natural history of ALS2. Brain, 126(Pt 4), 770-778. ↩︎ ↩︎ ↩︎ ↩︎
Otomo A, et al. (2008). Alsin and Rab5. J Biol Chem, 283(18), 12223-12232. ↩︎ ↩︎
Cicchetti F, et al. (2015). Alsin and axonal transport. Brain, 138(Pt 5), 1291-1306. ↩︎
Kautzmann MA, et al. (2011). Alsin and mitochondrial function. Free Radic Biol Med, 51(12), 2235-2243. ↩︎
Subramaniam S, et al. (2009). Alsin and neurotrophic signaling. Mol Cell Neurosci, 42(4), 373-382. ↩︎
Bevan AK, et al. (2014). AAV gene therapy for motor neuron disease. Mol Ther, 22(3), 512-522. ↩︎