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The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis

An Erratum to this article was published on 01 November 2001

Abstract

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. 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).

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Figure 1: JPLS pedigrees.
Figure 2: Deletion mutations in ALS2 in families 1212 (A46fs×50) and 9397 (L623fs×646).
Figure 3: Expression of ALS2.
Figure 4: Alsin domains.
Figure 5: Alsin homologies.

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References

  1. Pringle, C.E. et al. Primary lateral sclerosis: clinical features, neuropathology and diagnostic criteria. Brain 115, 495–520 (1992).

    Article  Google Scholar 

  2. Charcot, J.M. Sclerose des cordons laeraux de la moelle epinière, chez une femme hystèrique, atteinte de contracture permanente des quatre members. Bull. Soc. Med. Hop. Paris 2, 24–42 (1965).

    Google Scholar 

  3. Erb, W.A. Über einen wenig bekannten spinalen symptomenkomplex. Berl. Klin. Wochenschr 12, 357–359 (1975).

    Google Scholar 

  4. Stark, F.M. & Moersch, F.P. Primary lateral sclerosis. J. Nerv. Ment. Dis. 102, 332–352 (1945).

    Article  Google Scholar 

  5. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J. Neurol. Sci. 124, 96–107 (1994).

  6. Hudson, A.J. et al. Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis. Brain Res. Bull. 30, 359–364 (1993).

    Article  CAS  Google Scholar 

  7. Beal, M.F. & Richardson, E.P. Primary lateral sclerosis: a case report. Arch. Neurol. 38, 630–633 (1981).

    Article  CAS  Google Scholar 

  8. Fisher, C.M. Pure spastic paralysis of corticospinal origin. Can. J. Neuro. Sci. 4, 251–258 (1977).

    Article  CAS  Google Scholar 

  9. Russo, L.S. Jr. Clinical and electrophysiological studies in primary lateral sclerosis. Arch. Neurol. 39, 662–664 (1982).

    Article  Google Scholar 

  10. Sotaniemi, K.A. & Myllylla, V.V. Primary lateral sclerosis, a debated entity. Acta Neurol. Scand. 71, 334–336 (1985).

    Article  CAS  Google Scholar 

  11. Younger, D.S. et al. Primary lateral sclerosis: a clinical diagnosis reemerges. Arch. Neurol. 45, 1304–1307 (1988).

    Article  CAS  Google Scholar 

  12. Gascon, G.G. et al. Familial childhood primary lateral sclerosis with associated gaze paresis. Neuorpediatrics 26, 313–319 (1995).

    Article  CAS  Google Scholar 

  13. Heene, R., Kolander, D. & Knisatschek, H. Die chronisch-progrediente spinobulbäre spastik (primare lateralsklerose). Fortschr. Neurol. Psychiat. 64, 192–203 (1996).

    Article  CAS  Google Scholar 

  14. Brown, W.F., Ebers, G.C., Hudson, A.J., Pringle, C.E. & Veitch, J. Motor evoked responses in primary lateral sclerosis. Muscle Nerve 15, 626–629 (1992).

    Article  CAS  Google Scholar 

  15. Grunnet, M.L., Leicher, C., Zimmerman, A., Zalneraitis, E. & Barwick, M. Primary lateral sclerosis in a child. Neurology 39, 1530–1532 (1989).

    Article  CAS  Google Scholar 

  16. Lerman-Sagie, T., Filliano, J., Smith, D.W. & Korson, M. Infantile onset of hereditary ascending spastic paralysis with bulbar involvement. J. Child. Neurol. 11, 54–57 (1996).

    Article  CAS  Google Scholar 

  17. Siddique, T. et al. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. New Engl. J. Med. 324, 1381–1384 (1991).

    Article  CAS  Google Scholar 

  18. Hentati, A. et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33–q35. Nature Genet. 7, 425–428 (1994).

    Article  CAS  Google Scholar 

  19. Hentati, A. et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 2, 55–60 (1998).

    Article  CAS  Google Scholar 

  20. Chance, P. F. et al. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am. J. Hum. Genet. 62, 633–640 (1998).

    Article  CAS  Google Scholar 

  21. Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

    Article  CAS  Google Scholar 

  22. Deng, H.-X. et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 261, 1047–1051 (1993).

    Article  CAS  Google Scholar 

  23. Ben Hamida, M., Hentati, F. & Ben Hamida, C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Brain 113, 347–363 (1990).

    Article  Google Scholar 

  24. Cottingham, R.W. Jr, Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

    Google Scholar 

  25. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl Acad. Sci. USA 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

  26. Schaffer, A.A., Gupta, S.K., Shriram, K. & Cottingham, R.W. Jr. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).

    Article  CAS  Google Scholar 

  27. Ott, J. Analysis of Human Genetic Linkage revised edition 194–216 (Johns Hopkins University, Baltimore, 1991).

    Google Scholar 

  28. Deng, H.X. et al. Chromosome-band-specific painting: chromosome in situ suppression hybridization using PCR products from a microdissected chromosome band as a probe pool. Hum. Genet. 89, 13–17 (1992).

    Article  CAS  Google Scholar 

  29. Sonnhammer, E.L.L., Eddy, S.R., Birney, E., Bateman, A. & Durbin, R. Pfam: multiple sequence alignments and HMM-profiles of protein domains. Nucleic Acids Res. 26, 320–322 (1998).

    Article  CAS  Google Scholar 

  30. Delcher, A.L. Alignment of whole genomes. Nucleic Acids Res. 27, 2369–2376 (1999).

    Article  CAS  Google Scholar 

  31. Schultz, J., Milpetz, F., Bork, P. & Ponting, C.P. SMART: identification and annotation of domains from signalling and extracellular protein sequences. Nucleic Acids Res. 27, 229–232 (1999).

    Article  Google Scholar 

  32. Lemmon, M.A. and Ferguson, K.M. Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Biochem. J. 350, Pt 1: 1–18 (2000).

    Article  CAS  Google Scholar 

  33. Takeshima, H. et al. Junctophilins: a novel family of junctional membrane complex proteins. Mol. Cell. 6, 11–22 (2000).

    CAS  Google Scholar 

  34. Lehman, A. et al. A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice. Proc. Natl Acad. Sci. USA 95, 9436–9441 (1998).

    Article  CAS  Google Scholar 

  35. Kahana, J.A. & Cleveland, D.W. Some importin news about spindle assembly. Science 291, 1718–1719 (2001).

    Article  CAS  Google Scholar 

  36. Roepman, R. et al. Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1. Hum. Mol. Genet. 5, 1035–1041 (1996).

    Article  CAS  Google Scholar 

  37. Yan, D. et al. Biochemical characterization and subcellular localization of the mouse retinitis pigmentosa GTPase regulator (mRpgr). J. Biol. Chem. 273, 19656–19663 (1998).

    Article  CAS  Google Scholar 

  38. Rosa, J.L. & Casaroli-Marano, R.P. A giant protein that stimulates guanine nucleotide exchange on ARF1 and Rab proteins forms a cytosolic ternary complex with clathrin and Hsp70. Oncogene 15, 1–6 (1997).

    Article  CAS  Google Scholar 

  39. Bar-Sagi, D. & Hall, A. Ras and Rho GTPases: a family reunion. Cell 103, 227–238 (2000).

    Article  CAS  Google Scholar 

  40. Hama, H., Tall, G.G. & Horazdovsky, B.F. Vps9p is a guanine nucleotide exchange factor involved in vesicle-mediated vacuolar protein transport. J. Biol. Chem. 274, 15284–15291 (1999).

    Article  CAS  Google Scholar 

  41. Rampoldi, L. et al. A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nature Genet. 28, 119–120 (2001).

    Article  CAS  Google Scholar 

  42. Mourelatos, Z., Gonatas, N.K., Stieber, A., Gurney, M.E. & Dal Canto, M.C. The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc. Natl Acad. Sci. USA 93, 5472–5477 (1996).

    Article  CAS  Google Scholar 

  43. Gurney, M.E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1172–1175 (1994).

    Article  Google Scholar 

  44. Brown, R.H. SOD1 aggregates in ALS: cause, correlate or consequence? Nature Med. 4, 1362–1364 (1998).

    Article  CAS  Google Scholar 

  45. Cleveland, D.W. From Charcot to SOD1: mechanisms of selective motor neuron death in ALS. Neuron 24, 515–520 (1999).

    Article  CAS  Google Scholar 

  46. Deng, H.X. and Siddique, T. Transgenic mouse models and human neurodegenerative disorders. Arch. Neurol. 57, 1695–1702 (2000).

    Article  CAS  Google Scholar 

  47. Atawater, J.A., Wisdom, R. & Verma, I.M. Regulated mRNA stability. Annu. Rev. Genet. 24, 519–541 (1990).

    Article  Google Scholar 

  48. Shoshani, T. et al. Similar levels of mRNA from the W1282X and the DeltaF508 cystic fibrosis alleles, in nasal epithelial cells. J. Clin. Invest. 93, 1502–1507 (1994).

    Article  CAS  Google Scholar 

  49. Haardt, M., Benharourga, M., Lechardeur, D., Kartner, N. & Lukacs, L. C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. J. Biol. Chem. 274, 21873–21877 (1999).

    Article  CAS  Google Scholar 

  50. Dunnen, J.T. & Antonarakis, S.E. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Human Mutat. 15, 7–12 (2000).

    Article  Google Scholar 

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Acknowledgements

We are deeply indebted to the members of the Tunisian and Saudi Arabian families for their participation. This study was funded by grants from the NIH (PO1 NS21442, RO1 NS37912 and RO1 NS40308), the Les Turner ALS Foundation, Grant Healthcare Foundation, the Michael Jordan Foundation and the Ralph and Marian Falk Medical Research Trust. K.O. is a Muscular Dystrophy Association funded fellow and W.-Y.H. is a Muriel Heller Fellow.

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Correspondence to Teepu Siddique.

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Yang, Y., Hentati, A., Deng, HX. et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29, 160–165 (2001). https://doi.org/10.1038/ng1001-160

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