Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis*

15 July 2012 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,…

15 July 2012

  • 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 D. Glass,
  • Gabriele Siciliano
  • et al.

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 years1, 2, 3, 4, 5, 6, 7, 8, 9, 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.

Nature