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Gene Review

ALS2  -  amyotrophic lateral sclerosis 2 (juvenile)

Homo sapiens

Synonyms: ALS2CR6, ALSJ, Alsin, Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 6 protein, Amyotrophic lateral sclerosis 2 protein, ...
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Disease relevance of ALS2


High impact information on ALS2

  • Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2 [1].
  • We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33 [6].
  • Two papers in this issue of Nature Genetics describe homozygous mutations in a new gene on chromosome 2q33 in 4 families of Arabian origin with a rare form of juvenile onset ALS (ALS2) [7].
  • The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs) [6].
  • The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis [6].

Biological context of ALS2


Anatomical context of ALS2

  • Thus, a perturbation of endosomal dynamics caused by loss of ALS2 rab5GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases [12].
  • Further, the DH/PH domain in the middle portion of ALS2 protein enhances the VPS9 domain-mediated endosome fusions [12].
  • Endogenous ALS2 is shown here to be enriched in nervous tissue and to be peripherally bound to the cytoplasmic face of endosomal membranes, an association that requires the amino-terminal "RCC1 (regulator of chromatin condensation)-like" GEF domain [13].
  • Disease-causing mutants and a naturally truncated isoform of ALS2 are shown to be rapidly degraded when expressed in cultured human cells, including lymphocytes derived from patients with ALS2 mutations [13].
  • Finally, we demonstrate that ALS2 promotes neurite outgrowth [14].

Associations of ALS2 with chemical compounds

  • ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics [12].
  • This homozygous G669A mutation in exon 4 is predicted to result in a tyrosine substitution at cysteine 156 of the RCC1 (regulator of chromatin condensation)-like domain, encoding a putative guanine exchange factor for Ran guanosine triphosphatase, leading to a loss of ALS2 function due to instability of mutant protein [15].
  • Real-time RT-PCR analysis demonstrated that in maltose-containing medium, strain 2342 overexpressed ALS2 compared to wild-type cells; however no overexpression phenotype was apparent [16].
  • Real-time RT-PCR analysis of strain 2342 grown in glucose-containing medium (non-inducing conditions) showed that although ALS2 transcript levels were greatly reduced compared to wild-type cells, some ALS2 transcript remained [16].
  • Mutant alsin induced neuronal death itself and also significantly enhanced the apoptogenic effect of NMDA and staurosporine [9].

Regulatory relationships of ALS2

  • The remaining ALS2 allele was placed under control of the C. albicans MAL2 promoter to create an als2Delta/PMAL2-ALS2 strain (named 2342) [16].

Other interactions of ALS2

  • Among the up-regulated genes were ALS2 and ALS5 both of which encode proteins that provide an adherence function for C. albicans [17].
  • However, familial forms of ALS have been described--autosomal dominant forms (ALS1, ALS3), clinically indistinguishable from the sporadic form, and autosomal recessive forms with early onset and slower progression of symptoms (ALS2) [18].
  • METHODS: DNA from 95 unrelated familial, 95 unrelated sporadic, and 11 early-onset ALS patients was screened for mutations in ALS2 by denaturing high-performance liquid chromatography and direct sequencing of polymerase chain reaction-amplified fragments [19].
  • Computational genomic analysis identified ALS2CL, which is a novel protein highly homologous to the C-terminal region of ALS2 [20].
  • Procedures are presented in this chapter for the expression, purification, and biochemical characterization of the individual GEF domains of Alsin [21].

Analytical, diagnostic and therapeutic context of ALS2

  • By RT-PCR, ALS2 and 5, similar to the microarray data, were significantly increased in infected cells at 3 h [17].
  • METHODS: ALS2-deficient mice were generated by gene targeting [5].


  1. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Hadano, S., Hand, C.K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R.S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D.A., Kwiatkowski, T., Hosler, B.A., Sagie, T., Skaug, J., Nasir, J., Brown, R.H., Scherer, S.W., Rouleau, G.A., Hayden, M.R., Ikeda, J.E. Nat. Genet. (2001) [Pubmed]
  2. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F.M., di Capua, M., Bertini, E., Boespflug-Tanguy, O. Am. J. Hum. Genet. (2002) [Pubmed]
  3. Homo-oligomerization of ALS2 through its unique carboxyl-terminal regions is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking. Kunita, R., Otomo, A., Mizumura, H., Suzuki, K., Showguchi-Miyata, J., Yanagisawa, Y., Hadano, S., Ikeda, J.E. J. Biol. Chem. (2004) [Pubmed]
  4. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. Devon, R.S., Helm, J.R., Rouleau, G.A., Leitner, Y., Lerman-Sagie, T., Lev, D., Hayden, M.R. Clin. Genet. (2003) [Pubmed]
  5. Progressive spinal axonal degeneration and slowness in ALS2-deficient mice. Yamanaka, K., Miller, T.M., McAlonis-Downes, M., Chun, S.J., Cleveland, D.W. Ann. Neurol. (2006) [Pubmed]
  6. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Yang, Y., Hentati, A., Deng, H.X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.Y., Ouahchi, K., Yan, J., Azim, A.C., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. Nat. Genet. (2001) [Pubmed]
  7. Genetic inroads in familial ALS. Shaw, P.J. Nat. Genet. (2001) [Pubmed]
  8. Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amyotrophic lateral sclerosis. Nagano, I., Murakami, T., Shiote, M., Manabe, Y., Hadano, S., Yanagisawa, Y., Ikeda, J.E., Abe, K. Neurol. Res. (2003) [Pubmed]
  9. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Panzeri, C., De Palma, C., Martinuzzi, A., Daga, A., De Polo, G., Bresolin, N., Miller, C.C., Tudor, E.L., Clementi, E., Bassi, M.T. Brain (2006) [Pubmed]
  10. A yeast artificial chromosome-based physical map of the juvenile amyotrophic lateral sclerosis (ALS2) critical region on human chromosome 2q33-q34. Hadano, S., Nichol, K., Brinkman, R.R., Nasir, J., Martindale, D., Koop, B.F., Nicholson, D.W., Scherer, S.W., Ikeda, J.E., Hayden, M.R. Genomics (1999) [Pubmed]
  11. Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families. Lesca, G., Eymard-Pierre, E., Santorelli, F.M., Cusmai, R., Di Capua, M., Valente, E.M., Attia-Sobol, J., Plauchu, H., Leuzzi, V., Ponzone, A., Boespflug-Tanguy, O., Bertini, E. Neurology (2003) [Pubmed]
  12. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Otomo, A., Hadano, S., Okada, T., Mizumura, H., Kunita, R., Nishijima, H., Showguchi-Miyata, J., Yanagisawa, Y., Kohiki, E., Suga, E., Yasuda, M., Osuga, H., Nishimoto, T., Narumiya, S., Ikeda, J.E. Hum. Mol. Genet. (2003) [Pubmed]
  13. Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Yamanaka, K., Vande Velde, C., Eymard-Pierre, E., Bertini, E., Boespflug-Tanguy, O., Cleveland, D.W. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  14. ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth. Tudor, E.L., Perkinton, M.S., Schmidt, A., Ackerley, S., Brownlees, J., Jacobsen, N.J., Byers, H.L., Ward, M., Hall, A., Leigh, P.N., Shaw, C.E., McLoughlin, D.M., Miller, C.C. J. Biol. Chem. (2005) [Pubmed]
  15. Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis. Eymard-Pierre, E., Yamanaka, K., Haeussler, M., Kress, W., Gauthier-Barichard, F., Combes, P., Cleveland, D.W., Boespflug-Tanguy, O. Ann. Neurol. (2006) [Pubmed]
  16. Analysis of the Candida albicans Als2p and Als4p adhesins suggests the potential for compensatory function within the Als family. Zhao, X., Oh, S.H., Yeater, K.M., Hoyer, L.L. Microbiology (Reading, Engl.) (2005) [Pubmed]
  17. Gene transcription studies of Candida albicans following infection of HEp2 epithelial cells. Sandovsky-Losica, H., Chauhan, N., Calderone, R., Segal, E. Med. Mycol. (2006) [Pubmed]
  18. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Hentati, A., Bejaoui, K., Pericak-Vance, M.A., Hentati, F., Speer, M.C., Hung, W.Y., Figlewicz, D.A., Haines, J., Rimmler, J., Ben Hamida, C. Nat. Genet. (1994) [Pubmed]
  19. Mutation screening of the ALS2 gene in sporadic and familial amyotrophic lateral sclerosis. Hand, C.K., Devon, R.S., Gros-Louis, F., Rochefort, D., Khoris, J., Meininger, V., Bouchard, J.P., Camu, W., Hayden, M.R., Rouleau, G.A. Arch. Neurol. (2003) [Pubmed]
  20. Purification and functional analyses of ALS2 and its homologue. Hadano, S., Ikeda, J.E. Meth. Enzymol. (2005) [Pubmed]
  21. Biochemical characterization of Alsin, a Rab5 and Rac1 guanine nucleotide exchange factor. Topp, J.D., Carney, D.S., Horazdovsky, B.F. Meth. Enzymol. (2005) [Pubmed]
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