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  • 2012 (1)

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Search Results for all work with filters:

  • Rossoll, Wilfried
  • Leclerc, Ashley Lyn
  • Meininger, Vincent
  • Biology, Cell
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Article

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

by Chi-Hong Wu; Claudia Fallini; Nicola Ticozzi; Pamela J. Keagle; Peter C. Sapp; Katarzyna Piotrowska; Patrick Lowe; Max Koppers; Diane McKenna-Yasek; Desiree M. Baron; Jason E. Kost; Paloma Gonzalez-Perez; Andrew D. Fox; Jenni Adams; Franco Taroni; Cinzia Tiloca; Ashley Lyn Leclerc; Shawn C. Chafe; Dev Mangroo; Melissa J. Moore; Jill A. Zitzewitz; Zuo-Shang Xu; Leonard H. van den Berg; Jonathan Glass; Gabriele Siciliano; Elizabeth T. Cirulli; David B. Goldstein; Francois Salachas; Vincent Meininger; Wilfried Rossoll; Antonia Ratti; Cinzia Gellera; Daryl A. Bosco; Gary Bassell; Vincenzo Silani; Vivian E. Drory; Robert H. Brown; John E. Landers

2012

Subjects
  • Biology, Cell
  • Biology, Molecular
  • Health Sciences, General
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Abstract:Close

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.
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