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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

Nature Genetics volume 29, pages 160–165 (2001)Cite this article

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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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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Authors and Affiliations

  1. Department of Neurology, Northwestern University Medical School, Chicago, Illinois, USA

    Yi Yang, Afif Hentati, Han-Xiang Deng, Toru Sasaki, Makito Hirano, Wu-Yen Hung, Karim Ouahchi, Jianhua Yan, Anser C. Azim, Natalie Cole & Teepu Siddique

  2. King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

    Omar Dabbagh

  3. Division of Pediatric Neurology, Brown University, Providence, Rhode Island, USA

    Generoso Gascon

  4. King Fahad Military Hospital, Jeddah, Saudi Arabia

    Ayesha Yagmour

  5. Institute of Neurology, Tunis, Tunisia

    Mongi Ben-Hamida & Fayçal Hentati

  6. Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA

    Margaret Pericak-Vance

  7. Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois, USA

    Teepu Siddique

  8. Northwestern University Institute of Neuroscience, Chicago, Illinois, USA

    Teepu Siddique

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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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