@article{10e1a9b4a53047eaa3e3f2b38f624422,
title = "Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis",
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.",
author = "Wu, {Chi Hong} and Claudia Fallini and Nicola Ticozzi and Keagle, {Pamela J.} and Sapp, {Peter C.} and Katarzyna Piotrowska and Patrick Lowe and Max Koppers and Diane McKenna-Yasek and Baron, {Desiree M.} and Kost, {Jason E.} and Paloma Gonzalez-Perez and Fox, {Andrew D.} and Jenni Adams and Franco Taroni and Cinzia Tiloca and Leclerc, {Ashley Lyn} and Chafe, {Shawn C.} and Dev Mangroo and Moore, {Melissa J.} and Zitzewitz, {Jill A.} and Xu, {Zuo Shang} and {Van Den Berg}, {Leonard H.} and Glass, {Jonathan D.} and Gabriele Siciliano and Cirulli, {Elizabeth T.} and Goldstein, {David B.} and Francois Salachas and Vincent Meininger and Wilfried Rossoll and Antonia Ratti and Cinzia Gellera and Bosco, {Daryl A.} and Bassell, {Gary J.} and Vincenzo Silani and Drory, {Vivian E.} and Brown, {Robert H.} and Landers, {John E.}",
note = "Funding Information: Acknowledgements Support was provided by the ALS Therapy Alliance, Project ALS, P2ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation and a Francesco Caleffi donation (N.T. and V.S.). Grant support was provided by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (1R01NS065847 (J.E.L.), 1R01NS050557 (R.H.B.), and RC2-NS070-342 (R.H.B.)), Muscular Dystrophy Association (MDA173851 (W.R.)) and AriSLA co-financed with support of {\textquoteleft}5x1000{\textquoteright}—Healthcare research of the Ministry of Health (EXOMEFALS (N.T., C.G., V.S. and J.E.L.)). Support was provided by an SMA Europe fellowship to C.F. P.C.S. was supported through the auspices of H. R. Horvitz (Massachusetts Instituteof Technology),an investigator of the Howard Hughes Medical Institute. We thank the laboratory of S. Doxsey, the UMass Medical School Digital Light Microscopy Core, the UMass Medical School Deep Sequencing Core, the Emory University Neuropathology Core, and M. Gearing and D. Cooper for their assistance.",
year = "2012",
month = aug,
day = "23",
doi = "10.1038/nature11280",
language = "English (US)",
volume = "488",
pages = "499--503",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7412",
}