Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

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. MooreJill A. Zitzewitz, Zuo Shang Xu, Leonard H. Van Den Berg, Jonathan D. Glass, Gabriele Siciliano, Elizabeth T. Cirulli, David B. Goldstein, Francois Salachas, Vincent Meininger, Wilfried Rossoll, Antonia Ratti, Cinzia Gellera, Daryl A. Bosco, Gary J. Bassell, Vincenzo Silani, Vivian E. Drory, Robert H. Brown, John E. Landers

Research output: Contribution to journalArticlepeer-review

375 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)499-503
Number of pages5
Issue number7412
StatePublished - Aug 23 2012

ASJC Scopus subject areas

  • General


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