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 Moore, Jill 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 Jr, John E Landers, 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, 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 Jr, John E Landers
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.
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References
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Source: PubMed