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Genetics Home Reference: your guide to understanding genetic conditions
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ALS2

Reviewed August 2012

What is the official name of the ALS2 gene?

The official name of this gene is “amyotrophic lateral sclerosis 2 (juvenile).”

ALS2 is the gene's official symbol. The ALS2 gene is also known by other names, listed below.

What is the normal function of the ALS2 gene?

The ALS2 gene provides instructions for making a protein called alsin. Alsin is produced in a wide range of tissues, with highest amounts in the brain. This protein is particularly abundant in motor neurons, the specialized nerve cells in the brain and spinal cord that control the movement of muscles.

Alsin appears to have many functions, only a few of which are known. Alsin turns on (activates) multiple proteins called GTPases that convert a molecule called GTP into another molecule called GDP. GTPases play important roles in cell division, the process by which cells mature to carry out specific functions (differentiation), and the self-destruction of cells (apoptosis). Alsin is also thought to play a role in cell membrane organization and the transport of molecules from the cell membrane to the interior of the cell (endocytosis). Research findings also suggest that alsin may play a role in the development of axons and dendrites, which are specialized outgrowths from nerve cells that are essential for the transmission of nerve impulses.

Does the ALS2 gene share characteristics with other genes?

The ALS2 gene belongs to a family of genes called ARHGEF (Rho guanine nucleotide exchange factors).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the ALS2 gene related to health conditions?

amyotrophic lateral sclerosis - caused by mutations in the ALS2 gene

At least eight mutations in the ALS2 gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive movement problems and muscle wasting caused by motor neuron death. ALS2 gene mutations are often associated with the juvenile form of ALS, which develops in a person's teens or twenties. Most of these mutations delete single DNA building blocks (nucleotides) in the ALS2 gene, which alters the instructions for producing alsin. As a result of ALS2 gene mutations, alsin does not function correctly or does not function at all.

It is unclear how the loss of functional alsin protein causes ALS. A reduction in alsin function may disrupt the activation of GTPases and prevent the necessary cell functions that they facilitate. Additionally, a lack of functional alsin may impair the movement of essential molecules into cells or alter the development of axons and dendrites. Researchers suggest that the long axons of motor neurons may be particularly sensitive to altered development. It is likely that a combination of these deficits in function eventually cause motor neurons to die, leading to the signs and symptoms of ALS.

infantile-onset ascending hereditary spastic paralysis - caused by mutations in the ALS2 gene

Researchers have identified several ALS2 gene mutations that cause infantile-onset ascending hereditary spastic paralysis, a disorder characterized by progressive weakness and stiffness of muscles in the arms, legs, and face that begins within the first 2 years of life. The mutations that cause this condition change or delete one or more nucleotides, which alters the instructions for producing alsin. As a result, alsin is unstable and is broken down rapidly by the cell.

It is unclear how the loss of alsin protein causes infantile-onset ascending hereditary spastic paralysis. Loss of alsin may disrupt the movement of essential molecules within cells or alter the development of axons and dendrites. Long axons are thought to be particularly sensitive to altered development. The loss of functional alsin leads to a decline in motor neuron function causing these nerve cells to die, leading to the signs and symptoms of infantile-onset ascending hereditary spastic paralysis.

juvenile primary lateral sclerosis - caused by mutations in the ALS2 gene

Researchers have identified three mutations in the ALS2 gene that cause juvenile primary lateral sclerosis, which is characterized by progressive weakness and stiffness of muscles in the arms, legs, and face that typically begins in childhood. Two of the mutations that cause this disorder delete nucleotides, and one mutation replaces one nucleotide with an incorrect nucleotide. These mutations alter the instructions for producing alsin. As a result, alsin is unstable and is broken down rapidly by the cell, or it is disabled and cannot function properly.

It is unclear how the loss of functional alsin protein causes juvenile primary lateral sclerosis. Loss of alsin may result in a disruption of the movement of molecules within cells or impair the development of axons and dendrites. Researchers suggest that motor neurons and their long axons may be particularly vulnerable to changes in cell development. As a result, motor neuron function declines and eventually these nerve cells die, leading to the signs and symptoms of juvenile primary lateral sclerosis.

Where is the ALS2 gene located?

Cytogenetic Location: 2q33.1

Molecular Location on chromosome 2: base pairs 201,700,262 to 201,781,171

The ALS2 gene is located on the long (q) arm of chromosome 2 at position 33.1.

The ALS2 gene is located on the long (q) arm of chromosome 2 at position 33.1.

More precisely, the ALS2 gene is located from base pair 201,700,262 to base pair 201,781,171 on chromosome 2.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about ALS2?

You and your healthcare professional may find the following resources about ALS2 helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the ALS2 gene or gene products?

  • ALS2CR6
  • ALS2_HUMAN
  • ALSJ
  • IAHSP
  • KIAA1563
  • PLSJ

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding ALS2?

apoptosis ; axons ; cell ; cell division ; cell membrane ; differentiation ; DNA ; endocytosis ; gene ; GTP ; hereditary ; juvenile ; molecule ; motor ; motor neuron ; mutation ; neuron ; nucleotide ; protein ; sclerosis ; wasting

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Devon RS, Helm JR, Rouleau GA, Leitner Y, Lerman-Sagie T, Lev D, Hayden MR. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. Clin Genet. 2003 Sep;64(3):210-5. (http://www.ncbi.nlm.nih.gov/pubmed/12919135?dopt=Abstract)
  • Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Capua M, Bertini E, Boespflug-Tanguy O. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet. 2002 Sep;71(3):518-27. Epub 2002 Jul 26. (http://www.ncbi.nlm.nih.gov/pubmed/12145748?dopt=Abstract)
  • Eymard-Pierre E, Yamanaka K, Haeussler M, Kress W, Gauthier-Barichard F, Combes P, Cleveland DW, Boespflug-Tanguy O. Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis. Ann Neurol. 2006 Jun;59(6):976-80. (http://www.ncbi.nlm.nih.gov/pubmed/16718699?dopt=Abstract)
  • Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Nov;7(11):616-30. doi: 10.1038/nrneurol.2011.152. Review. (http://www.ncbi.nlm.nih.gov/pubmed/22051914?dopt=Abstract)
  • Gros-Louis F, Meijer IA, Hand CK, Dubé MP, MacGregor DL, Seni MH, Devon RS, Hayden MR, Andermann F, Andermann E, Rouleau GA. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol. 2003 Jan;53(1):144-5. (http://www.ncbi.nlm.nih.gov/pubmed/12509863?dopt=Abstract)
  • Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001 Oct;29(2):166-73. (http://www.ncbi.nlm.nih.gov/pubmed/11586298?dopt=Abstract)
  • Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15478096?dopt=Abstract)
  • Millecamps S, Gentil BJ, Gros-Louis F, Rouleau G, Julien JP. Alsin is partially associated with centrosome in human cells. Biochim Biophys Acta. 2005 Aug 15;1745(1):84-100. Epub 2005 Jan 19. (http://www.ncbi.nlm.nih.gov/pubmed/16085057?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/57679)
  • 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 JE. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum Mol Genet. 2003 Jul 15;12(14):1671-87. (http://www.ncbi.nlm.nih.gov/pubmed/12837691?dopt=Abstract)
  • Panzeri C, De Palma C, Martinuzzi A, Daga A, De Polo G, Bresolin N, Miller CC, Tudor EL, Clementi E, Bassi MT. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain. 2006 Jul;129(Pt 7):1710-9. Epub 2006 May 2. (http://www.ncbi.nlm.nih.gov/pubmed/16670179?dopt=Abstract)
  • Tudor EL, Perkinton MS, Schmidt A, Ackerley S, Brownlees J, Jacobsen NJ, Byers HL, Ward M, Hall A, Leigh PN, Shaw CE, McLoughlin DM, Miller CC. ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth. J Biol Chem. 2005 Oct 14;280(41):34735-40. Epub 2005 Jul 26. (http://www.ncbi.nlm.nih.gov/pubmed/16049005?dopt=Abstract)
  • Yamanaka K, Vande Velde C, Eymard-Pierre E, Bertini E, Boespflug-Tanguy O, Cleveland DW. Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16041-6. Epub 2003 Dec 10. (http://www.ncbi.nlm.nih.gov/pubmed/14668431?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: August 2012
Published: October 20, 2014