Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis : Nature : Nature Publishing Group

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis : Nature : Nature Publishing Group

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

• Chi-Hong Wu,¹
• Claudia Fallini,²
• Nicola Ticozzi,³
• Pamela J. Keagle,¹
• Peter C. Sapp,^{1, 4}
• Katarzyna Piotrowska,¹
• Patrick Lowe,¹
• Max Koppers,⁵
• Diane McKenna-Yasek,¹
• Desiree M. Baron,¹
• Jason E. Kost,¹
• Paloma Gonzalez-Perez,¹
• Andrew D. Fox,¹
• Jenni Adams,¹
• Franco Taroni,⁶
• Cinzia Tiloca,^{3, 7}
• Ashley Lyn Leclerc,¹
• Shawn C. Chafe,⁸
• Dev Mangroo,⁸
• Melissa J. Moore,⁹
• Jill A. Zitzewitz,¹⁰
• Zuo-Shang Xu,¹⁰
• Leonard H. van den Berg,⁵
• Jonathan D. Glass,¹¹
• Gabriele Siciliano,¹²
• Elizabeth T. Cirulli,¹³
• David B. Goldstein,¹³
• Francois Salachas,¹⁴
• Vincent Meininger,¹⁴
• Wilfried Rossoll,²
• Antonia Ratti,^{3, 15}
• Cinzia Gellera,⁶
• Daryl A. Bosco,¹
• Gary J. Bassell,^{2, 11}
• Vincenzo Silani,^{3, 15}
• Vivian E. Drory,¹⁶
• Robert H. Brown¹
• & John E. Landers¹
• et al.

• Affiliations
• Contributions
• Corresponding author

Journal name:

Nature

Year published:

(2012)

DOI:

doi:10.1038/nature11280

Received

12 January 2012

Accepted

31 May 2012

Published online

15 July 2012

 

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^{1, 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.