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    Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

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    Authors
    Wu, Chi-Hong
    Keagle, Pamela J.
    Sapp, Peter
    Piotrowska, Katarzyna
    Lowe, Patrick
    McKenna-Yasek, Diane
    Baron, Desiree
    Kost, Jason E.
    Gonzalez-Perez, Paloma
    Fox, Andrew D.
    Adams, Jenni
    Leclerc, Ashley Lyn
    Moore, Melissa J.
    Zitzewitz, Jill A.
    Xu, Zuoshang
    Bosco, Daryl
    Brown, Robert H. Jr.
    Landers, John E.
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    Student Authors
    Chi-Hong Wu
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Department of Neurology
    Document Type
    Journal Article
    Publication Date
    2012-08-23
    Keywords
    Genetics
    Genomics
    Molecular Biology
    Molecular Genetics
    Nervous System Diseases
    Neurology
    Neuroscience and Neurobiology
    
    Metadata
    Show full item record
    Link to Full Text
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575525/
    Abstract
    Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
    Source
    Nature. 2012 Aug 23;488(7412):499-503. doi: 10.1038/nature11280. Link to article on publisher's site
    DOI
    10.1038/nature11280
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/33463
    PubMed ID
    22801503
    Notes

    Full author list omitted for brevity. For the full list of authors, see article.

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    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1038/nature11280
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