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ALS2 gene

ALS2, alsin Rho guanine nucleotide exchange factor
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Normal Function

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 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). The GTPases play important roles in several cell processes. The GTPases that are activated by alsin are involved in the proper placement of the various proteins and fats that make up the cell membrane, the transport of molecules from the cell membrane to the interior of the cell (endocytosis), and the development of specialized structures called axons and dendrites that project from neurons and are essential for the transmission of nerve impulses.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

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Infantile-onset ascending hereditary spastic paralysis

At least 20 ALS2 gene mutations have been found to cause infantile-onset ascending hereditary spastic paralysis. This disorder is characterized by progressive weakness and stiffness of muscles in the legs, arms, neck, and head that begins within the first 2 years of life. Mutations in the ALS2 gene alter the instructions for making alsin, often resulting in the production of an abnormally short alsin protein that is unstable and rapidly broken down. It is unclear exactly how ALS2 gene mutations cause infantile-onset ascending hereditary spastic paralysis. Research suggests that a lack of alsin and the subsequent loss of GTPase functions, such as endocytosis and the development of axons and dendrites, contribute to the progressive atrophy of motor neurons that is characteristic of this condition.

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Juvenile primary lateral sclerosis

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.

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Other Names for This Gene

  • ALS2_HUMAN
  • ALS2CR6
  • ALSJ
  • amyotrophic lateral sclerosis 2 (juvenile)
  • IAHSP
  • KIAA1563
  • PLSJ

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

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. Citation on PubMed
  • 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. Citation on PubMed or Free article on PubMed Central
  • 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. Citation on PubMed
  • 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. Citation on PubMed
  • Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. Review. Citation on PubMed or Free article on PubMed Central
  • 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. Citation on PubMed
  • Racis L, Tessa A, Pugliatti M, Storti E, Agnetti V, Santorelli FM. Infantile-onset ascending hereditary spastic paralysis: a case report and brief literature review. Eur J Paediatr Neurol. 2014 Mar;18(2):235-9. doi: 10.1016/j.ejpn.2013.09.009. Epub 2013 Oct 9. Review. Citation on PubMed
  • Sheerin UM, Schneider SA, Carr L, Deuschl G, Hopfner F, Stamelou M, Wood NW, Bhatia KP. ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia. Neurology. 2014 Mar 25;82(12):1065-7. doi: 10.1212/WNL.0000000000000254. Epub 2014 Feb 21. Citation on PubMed or Free article on PubMed Central
  • 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. Citation on PubMed
  • 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. Citation on PubMed or Free article on PubMed Central
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