Scientists Identify the Gene Linked to Autosomal Recessive Juvenile ALS2

Oct 03, 2001, 01:00 ET from The ALS Association

    CALABASAS, Calif., Oct. 3 /PRNewswire/ -- In a multi-center, collaborative
 effort, two research groups have identified the gene responsible for the
 autosomal recessive form of ALS on chromosome 2 (juvenile ALS2 also known as
 type 3 autosomal recessive ALS).  One group includes investigators at
 NeuroGenes, Japan; Tokai University School of Medicine, Japan; McGill
 University and Montreal General Hospital Research Institute, Canada;
 University of British Columbia and Children's and Women's Hospital, Canada;
 University of Rochester Medical Center, and Massachusetts General Hospital,
 USA; Tel Aviv University, Israel; Department of Genetics, Ontario, Canada;
 University of Sheffield, United Kingdom; University of Ottawa, Canada.  The
 second group includes investigators at Northwestern University in Chicago,
 USA; King Faisal Specialist Hospital and Research Center, Saudi Arabia; Brown
 University, Rhode Island, USA; King Fahad Military Hospital, Saudia Arabia;
 Institute of Neurology, Tunisia; Duke University, North Carolina, USA.  These
 studies, partially funded by The ALS Association, have been published in the
 current issue of Nature Genetics*.
     Juvenile ALS2 is a rare form of ALS characterized by muscle atrophy,
 generalized fasciculations, and bulbar and pseudobulbar signs with normal
 sensory findings.  The disease has a mean age of onset of 12 years and
 progresses slowly for many years.  Two mutations in the same gene have been
 identified, one in a Tunisian family (A261del) and one in an unrelated Kuwaiti
 family (AG1548del).  The mutations shorten the protein removing the predicted
 regions important for protein function.  As the disease is autosomal recessive
 (two copies of the mutant gene must be present), these mutations are likely to
 result in a loss of function.
     "The discovery of a new gene linked to ALS is extremely exciting and will
 open up new avenues for ALS research," stated Lucie Bruijn, PhD, Vice
 President and Science Director for The ALS Association.   Added Bruijn, "The
 field is in desperate need for new leads to find therapies for the disease.
 Understanding the normal function of the gene product will provide new
 information about the disease mechanism and may shed new light on the role of
 the SOD1 mutations (the first ALS-linked mutations to be identified) in the
 disease process."
     The gene designated ALS2CR6 encodes a 184 kD protein (with the suggested
 name "alsin") of as yet unknown function.  Due to structural similarity with
 other proteins, it is speculated to act as a regulator/activator of particular
 proteins that modulate microtubule assembly, membrane organization and
 trafficking in cells including neurons (important features of axonal transport
 and structural organization of the cell).  The gene is found in neuronal cells
 throughout the brain and spinal cord, particularly in neurons in the
 hippocampus and dentate gyrus, cerebellar, Purkinje cells, neurons in the
 cerebral cortex and spinal gray matter including anterior horn cells.  It is
 unclear why motor neuron specific degeneration occurs and further studies to
 understand the function of the gene product is necessary.
     The discovery of a new gene for ALS is extremely important.
 Characterization of the protein product and its function will open up new
 avenues to understand the pathology of the disease, not only in the juvenile
 form of the disease but in other familial and sporadic forms.
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    * Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M.,
      Hung, W.-Y., Ouhchi, K., Yan, J., Azim, A.C., Cole, N., Gascon, G.,
      Yagmour, A., Ben-Hamida, M., Peicak-Vance, M., Hentati, F., Siddique, T.
      The gene encoding alsin, a protein with three guanine-nucleotide exchange
      factor domains, is mutated in a form of recessive amyotrophic lateral
      sclerosis. Nature Genetics 29, 160-165 (2001).
     * 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., Kwiatkwoski, T., Hosler, B.A, Sagie, T., Skaug, J.,
       Nasir, J., Brown, R.H.Jr., Scherer, S.W., Rouleau, G.A., Hayden, M.R.,
       Ikeda, J.-E.  A gene encoding a putative GTPase regulator is mutated in
       familial amyotrophic lateral sclerosis 2. Nature Genetics 29,
       166-173 (2001).
     Background information relating to ALS and the studies published in Nature
     What constitutes Juvenile ALS?
     Juvenile ALS is a rare form of ALS prevalent in populations of North
 Africa and the Middle East.  The onset, on average, is 12 years of age
 (typically manifests before age 25) and progresses very slowly.
     Why the focus on Juvenile ALS when it constitutes such a small population?
     Although clinical presentation of the variants of ALS appears different,
 motor neurons are affected in all cases.  There is likely to be a common
 pathway leading to motor neuron death.
     The discovery of new proteins linked to the disease may shed new light on
 the role of mutant SOD1 in disease.  It is possible that these proteins are in
 some way linked although this is currently unknown.
     Both proteins are expressed in many cell types and yet cause a highly
 selective clinical syndrome of motor system failure.  Multiple disease-linked
 genes may be involved in a common pathway leading to the selective loss of
 motor neurons.
     How do these studies affect those persons who currently have ALS?
     These studies open up new avenues for ALS research and there will be an
 aggressive effort to determine the function of this novel protein.
     Can this research result in effective treatments for ALS, juvenile or
     The discovery of multiple genes linked to ALS will potentially unravel the
 disease mechanism and provide new targets to develop therapies not only for
 the rarer forms of ALS, but also for sporadic forms of ALS.
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SOURCE The ALS Association