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A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2

Nature Genetics volume 29, pages 166–173 (2001)Cite this article

An Erratum to this article was published on 01 November 2001

An Erratum to this article was published on 01 November 2001

Abstract

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

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Figure 1: A transcript map of the 3-Mb region of human chromosome 2q33 containing the ALS2 candidate region.
Figure 2: Mutation detection in ALS2.
Figure 3: Northern blot analysis of ALS2 mRNA.
Figure 4: Amino-acid sequence analysis.
Figure 5: Expression of Als2 mRNA in adult mouse brain and spinal cord.

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References

  1. Siddique, T., Nijhawan, D. & Hentati, A. Molecular genetic basis of familial ALS. Neurology 47, S27–S35 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. 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 

  4. 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 

  5. Blair, I.P. et al. A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34. Neurogenetics 3, 1–6 (2000).

    CAS  Google Scholar 

  6. 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 

  7. Hosler, B.A. et al. Refined mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus (ALS2) on chromosome 2q33. Neurogenetics 2, 34–42 (1998).

    Article  CAS  Google Scholar 

  8. 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 

  9. Hosler, B.A. et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284, 1664–1669 (2000).

    Article  CAS  Google Scholar 

  10. 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 

  11. Hadano, S. et al. A yeast artificial chromosome-based physical map of the juvenile amyotrophic lateral sclerosis (ALS2) critical region on human chromosome 2q33–q34. Genomics 55, 106–112 (1999).

    Article  CAS  Google Scholar 

  12. Hadano, S. et al. Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33–q34: candidate genes for ALS2. Genomics 71, 200–213 (2001).

    Article  CAS  Google Scholar 

  13. Ohtsubo, M. et al. Isolation and characterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation. Genes Dev. 1, 585–593 (1987).

    Article  CAS  Google Scholar 

  14. Luo, L. Rho GTPases in neuronal morphogenesis. Nature Rev. Neurosci. 1, 173–180 (2000).

    Article  CAS  Google Scholar 

  15. Lerman-Sagie, T., Filiano, 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 

  16. Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M. & Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large protein in vitro. DNA Res. 7, 273–281 (2000).

    CAS  Google Scholar 

  17. Meindl, A. et al. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nature Genet. 13, 35–42 (1996).

    Article  CAS  Google Scholar 

  18. Renault, L. et al. The 1.7 Å crystal structure of the regulator of chromosome condensation (RCC1) reveals a seven-bladed propeller. Nature 392, 97–101 (1998).

    Article  CAS  Google Scholar 

  19. Soisson, S.M., Nimnual, A.S., Uy, M., Bar-Sagi, D. & Kuriyan, J. Crystal structure of the Dbl and pleckstrin homology domains from the human Son of sevenless protein. Cell 95, 259–268 (1998).

    Article  CAS  Google Scholar 

  20. 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 

  21. Horiuchi, H. et al. A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links nucleotide exchange to effector recruitment and function. Cell 90, 1149–1159 (1997).

    Article  CAS  Google Scholar 

  22. Tall, G.G., Barbieri, M.A., Stahl, P.D. & Horazdovsky, B.F. Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1. Dev. Cell 1, 73–82 (2001).

    Article  CAS  Google Scholar 

  23. Takeshima, H., Kamazaki, S., Nishi, M., Iino, M. & Kangawa, K. Junctophilins: a novel family of junctional membrane complex proteins. Mol. Cell 6, 11–22 (2000).

    CAS  Google Scholar 

  24. Carazo-Salas, R.E. et al. Generation of GTP-bound Ran by RCC1 is required for chromatin mitotic spindle formation. Nature 400, 178–181 (1999).

    Article  CAS  Google Scholar 

  25. Barrett, K., Leptin, M. & Settleman, J. The Rho GTPase and a putative RhoGEF mediate a signaling pathway for the cell shape changes in Drosophila gastrulation. Cell 91, 905–915 (1997).

    Article  CAS  Google Scholar 

  26. Martijn, F.B.G. et al. Identification of a novel, putative Rho-specific GDP/GTP exchange factor and a RhoA-binding protein: control of neuronal morphology. J. Cell Biol. 137, 1603–1613 (1997).

    Article  Google Scholar 

  27. Roepman, R. et al. The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors. Hum. Mol. Genet. 9, 2095–2105 (2000).

    Article  CAS  Google Scholar 

  28. Alam, M.R. et al. Kalirin, a cytosolic protein with spectrin-like and GDP/GTP exchange factor-like domains that interacts with peptidylglycine alpha-amidating monooxygenase, an integral membrane peptide-processing enzyme. J. Biol. Chem. 272, 12667–12675 (1997).

    Article  CAS  Google Scholar 

  29. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  CAS  Google Scholar 

  30. Culbertson, M.R. RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet. 15, 74–80 (1999).

    Article  CAS  Google Scholar 

  31. Collard, J.-F., Côté, F. & Julien, J.-P. Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature 375, 61–64 (1995).

    Article  CAS  Google Scholar 

  32. Williamson, T.L. & Cleveland, D.W. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nature Neurosci. 2, 50–56 (1999).

    Article  CAS  Google Scholar 

  33. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  34. Matsumoto, K. et al. Neuronal apoptosis inhibitory protein (NAIP) may enhance the survival of granulosa cells thus indirectly affecting oocyte survival. Mol. Repod. Dev. 54, 103–111 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients and other members of the ALS2 families for participating in this study; A.E. MacKenzie, R.G. Korneluk, I. Kanazawa, J.-C. Barbot and J.-C. Kaplan for providing control DNA samples; D. Rochefort for technical support; and all the members of our laboratories for helpful discussion and suggestions. This work was funded by the Japan Science and Technology Corporation, the Canadian Genetic Diseases Network, the Centre for Molecular Medicine and Therapeutics, the Nakabayashi Trust For ALS Research, the Japan Brain Foundation, the Grant-in-Aid for Scientific Research Priority Areas for the Ministry of Education, Science, Sports, and Culture (Japan), the Canadian Institute for Health Research, the Muscular Dystrophy Association (USA), the Amyotrophic Lateral Sclerosis Association, the National Institute for Neurological Disease (USA), National Institute for Aging (USA), Angel Fund for ALS Research (Boston, USA), Project ALS (New York, USA), Pierre L. DeBourgknecht ALS Research Foundation and Al-Athel ALS Foundation. M.R.H. is a holder of a Canada Research Chair. G.A.R. is supported by the Canadian Institute of Health Research. S.W.S. is a Scholar of the Medical Research Council of Canada. J.-E.I. is a scientific director of NeuroGenes/International Cooperative Research Project/Japan Science and Technology Corporation.

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Authors and Affiliations

  1. NeuroGenes, International Cooperative Research Project, Japan Science and Technology Corporation, Tokai University School of Medicine, Isehara, 259-1193, Kanagawa, Japan

    Shinji Hadano, Hitoshi Osuga, Yoshiko Yanagisawa, Asako Otomo, Natsuki Miyamoto & Joh-E Ikeda

  2. Department of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan

    Shinji Hadano, Hitoshi Osuga, Junko Showguchi-Miyata, Yoshinori Okada & Joh-E Ikeda

  3. Centre for Research in Neuroscience, McGill University, and Montreal General Hospital Research Institute, Montreal, Quebec, Canada

    Collette K. Hand & Guy A. Rouleau

  4. Department of Medical Genetics, and Centre for Molecular Medicine and Therapeutics, University of British Columbia and Children's and Women's Hospital, Vancouver, British Columbia, Canada

    Rebecca S. Devon, Roshni Singaraja, Jamal Nasir & Michael R. Hayden

  5. Departments of Neurology and Neurobiology & Anatomy, University of Rochester Medical Center, Rochester, New York, USA

    Denise A. Figlewicz

  6. Day Neuromuscular Research Laboratory, Navy Yard, Charlestown, Massachusetts, USA

    Thomas Kwiatkowski, Betsy A. Hosler & Robert H. Brown Jr

  7. Pediatric Neurology and Metabolic Neurogenetic Clinic, E. Wolfson Medical Center, Holon, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Tally Sagie

  8. Department of Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada

    Jennifer Skaug & Stephen W. Scherer

  9. Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK

    Jamal Nasir

  10. Department of Paediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

    Joh-E Ikeda

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  1. Shinji Hadano
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  21. Joh-E Ikeda
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Correspondence to Michael R. Hayden or Joh-E Ikeda.

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Hadano, S., Hand, C., Osuga, H. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 29, 166–173 (2001). https://doi.org/10.1038/ng1001-166

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