The Amyotrophic Lateral Sclerosis 2, juvenile (ALS2) gene encodes for ALSIN protein. Alsin is produced in a wide range of tissues, particularly in the motor neurons, the specialized nerve cells in the brain and spinal cord that control the movement of muscles. This protein has many functions, and only few are known. It plays a role as a guanine nucleotide exchange factor for the small GTPase RAB5, it localizes with RAB5 on early endosomal compartments, and it functions as a modulator for endosomal dynamics. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in the ALS2 gene cause several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis.
The ALS2 gene belongs to a family of genes called ARHGEF (Rho guanine nucleotide exchange factors). The ALS2 gene is located on human chromosome 2q33.2, from region 202,273,521 to 202,353,982, and has 34 exons; the transcript length is 6,644 bps. The Alsin protein consists of 1657 amino acids and weighs 183634 Da. The expression of the gene is normally found in various tissues and cells, including neurons throughout the brain and spinal cord.
Researchers have identified at least eight mutations in the ALS2 gene in association with various forms of Amyotrophic Lateral Sclerosis (ALS). All the mutations lead to unstable protein which breaks down rapidly by the cell, or it will disable the protein function. Four of these mutations have been identified to cause juvenile primary lateral sclerosis. In affected members three deletion mutations have been identified in exons 3, 5 and 9. Patients carrying the 1-bp deletion in exon 3 had more severe phenotype than others.
Five affected Kuwaiti patients with ALS2 from unrelated family have been studied by Hadano et al. (2001). Using haplotype analysis, a homozygous 2-bp deletion (c.1548delAG) in exon 5 has been found in two affected patients. Instead, the unaffected individuals carried the normal haplotype suggesting that the c.1548delAG is the cause of the ALS2 disease in the Kuwaiti patients. The Online Mendelian Inheritance in Man Database corrected the nomenclature of the mutation as c.1425delAG.
[See also: Tunisia > Hadano et al., 2001].
In three affected members of a consanguineous Saudi Arabian family with juvenile primary lateral sclerosis, Yang et al. (2001) identified a homozygous 2-bp deletion (c.1867delCT) in exon 9 of the ALS2 gene. This deletion led to a frameshift and premature stop codon 23 codons after the deletion site. A deletion occurred in codon 623 for leucine and the premature stop was created at codon 646.
Hentati et al. (1994) suggested that the ALS autosomal recessive form is located on chromosome 2q.33-q35 by performing the linkage analysis studies in affected Tunisian family.
Hadano et al. (2001) sequenced the ALS gene in 14 Tunisian family members affected with ALS2. Six intronic variations and two exonic sequence changes have been associated with the disease phenotype. One of these changes was a single nucleotide deletion (c.261delA) in exon 3, resulting in a frameshift and a premature stop codon.