Journal Article

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Fallini, Claudia, Kost, Jason E., Drory, Vivian E., Keagle, Pamela J., Meininger, Vincent, Ratti, Antonia, Sapp, Peter C., Fox, Andrew D., Taroni, Franco, Gellera, Cinzia, McKenna-Yasek, Diane, Piotrowska, Katarzyna, Gonzalez-Perez, Paloma, Leclerc, Ashley Lyn, Rossoll, Wilfried, Goldstein, David B., Brown Jr, Robert H., Adams, Jenni, Siciliano, Gabriele, Wu, Chi-Hong, Tiloca, Cinzia, Xu, Zuo-Shang, Landers, John E., Cirulli, Elizabeth T., Mangroo, Dev, Lowe, Patrick, Koppers, Max, Glass, Jonathan D., Baron, Desiree M., van den Berg, Leonard H., Salachas, Francois, Zitzewitz, Jill A., Bassell, Gary J., Ticozzi, Nicola, Bosco, Daryl A., Silani, Vincenzo, Chafe, Shawn C., Moore, Melissa J.

2012

Overview

Mutations in the profilin 1 ( PFN1 ) gene, which is crucial for the conversion of monomeric to filamentous actin, can cause familial amyotrophic lateral sclerosis, suggesting that alterations in cytoskeletal pathways contribute to disease pathogenesis. Genetics of familial amyotrophic lateral sclerosis In nearly half of the familial cases of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), the genetic basis remains unknown. These authors show that mutations in the profilin 1 ( PFN1 ) gene, which is essential for the conversion of monomeric to filamentous actin, can cause familial ALS. The available data suggest that alterations in cytoskeletal pathways contribute to the pathogenesis of ALS. The observation of PFN1 mutations in ALS has immediate implications for diagnostic testing of familial ALS cases and provides a novel potential target for the treatment of ALS. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/208/737 / 631/378/1689/1285 / Actins - metabolism / Amino Acid Sequence / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - diagnosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animals / Axons - metabolism / Axons - pathology / Biological and medical sciences / Causes of / Cells, Cultured / Classical genetics, quantitative genetics, hybrids / European Continental Ancestry Group - genetics / Exome - genetics / Female / Fundamental and applied biological sciences. Psychology / Gene mutation / Gene mutations / Genes / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Growth Cones - metabolism / Health aspects / High-Throughput Nucleotide Sequencing / Human / Humanities and Social Sciences / Humans / Jews - genetics / letter / Male / Mice / Models, Molecular / Molecular Sequence Data / Motor Neurons - cytology / Motor Neurons - metabolism / multidisciplinary / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Mutation - genetics / Pathogenesis / Pedigree / Polypeptides / Profilins - genetics / Profilins - metabolism / Protein Conformation / Proteins / Risk factors / Science / Ubiquitination