The gene, localized to chromosome 2, encodes a 184-kD protein (named ALS2 or alsin) with three putative guanine-nucleotide-exchange factor (GEF) domains.
Small GTP-binding proteins of the Ras superfamily act as molecular switches in signal transduction, affecting cytoskeletal dynamics, intracellular trafficking, and other important biological processes.
GEFs catalyze the dissociation of the tightly bound GDP from the small G protein in response to upstream signals.
Although widely expressed, the ALS2 protein is enriched in nervous tissue, where it is peripherally bound to the cytoplasmic face of endosomal membranes, an association that requires the amino-terminal RCC1-like GEF domain.
The G protein(s) upon which the ALS2 GEFs act has not been identified, although an initial report has shown that ALS2 can act in vitro as an exchange factor for Rab5a, which functions in endosomal trafficking.
All of the disease-causing mutants are highly unstable: This has led to the conclusion that early-onset motor neuron disease is caused by loss of activity of one or more of the GEF domains of this endosomal GEF.
Etiology
germline mutations of PLS2 in:
- juvenile amyotrophic lateral sclerosis locus 2 (ALS2) (205100)
- juvenile primary lateral sclerosis (PLSJ) (MIM.606353)
- infantile-onset ascending hereditary spastic paralysis (IAHSP) (MIM.607225)
See also
ALS genes
| SOD1 | ALS2 | SETX | VAPB | ANG | DCTN1 | MAPT |