The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the centra l nervous system. We have identified a familial juvenile PLS (JPLS) locus o verlapping the previously identified ALS2 locus on chromosome 2q33. We repo rt two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a comm on genetic origin. The predicted sequence of the protein (alsin) may indica te a mechanism for motor-neuron degeneration, as it may include several cel l-signaling motifs with known functions, including three associated with gu anine-nucleotide exchange factors for GTPases (GEFs).