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Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

WU, Chi-Hong ; FALLINI, Claudia ; KOST, Jason E ; GONZALEZ-PEREZ, Paloma ; FOX, Andrew D ; ADAMS, Jenni ; TARONI, Franco ; TILOCA, Cinzia ; LYN LECLERC, Ashley ; CHAFE, Shawn C ; MANGROO, Dev ; MOORE, Melissa J ; TICOZZI, Nicola ; ZITZEWITZ, Jill A ; XU, Zuo-Shang ; DEN BERG, Leonard H. Van ; GLASS, Jonathan D ; SICILIANO, Gabriele ; CIRULLI, Elizabeth T ; GOLDSTEIN, David B ; SALACHAS, Francois ; MEININGER, Vincent ; ROSSOLL, Wilfried ; KEAGLE, Pamela J ; RATTI, Antonia ; GELLERA, Cinzia ; BOSCO, Daryl A ; BASSELL, Gary J ; SILANI, Vincenzo ; DRORY, Vivian E ; BROWN, Robert H ; LANDERS, John E ; SAPP, Peter C ; PIOTROWSKA, Katarzyna ; LOWE, Patrick ; KOPPERS, Max ; MCKENNA-YASEK, Diane ; BARON, Desiree M

Nature (London), 2012-08, Vol.488 (7412), p.499-503 [Periódico revisado por pares]

London: Nature Publishing Group

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Título:
Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
Autor: WU, Chi-Hong ; FALLINI, Claudia ; KOST, Jason E ; GONZALEZ-PEREZ, Paloma ; FOX, Andrew D ; ADAMS, Jenni ; TARONI, Franco ; TILOCA, Cinzia ; LYN LECLERC, Ashley ; CHAFE, Shawn C ; MANGROO, Dev ; MOORE, Melissa J ; TICOZZI, Nicola ; ZITZEWITZ, Jill A ; XU, Zuo-Shang ; DEN BERG, Leonard H. Van ; GLASS, Jonathan D ; SICILIANO, Gabriele ; CIRULLI, Elizabeth T ; GOLDSTEIN, David B ; SALACHAS, Francois ; MEININGER, Vincent ; ROSSOLL, Wilfried ; KEAGLE, Pamela J ; RATTI, Antonia ; GELLERA, Cinzia ; BOSCO, Daryl A ; BASSELL, Gary J ; SILANI, Vincenzo ; DRORY, Vivian E ; BROWN, Robert H ; LANDERS, John E ; SAPP, Peter C ; PIOTROWSKA, Katarzyna ; LOWE, Patrick ; KOPPERS, Max ; MCKENNA-YASEK, Diane ; BARON, Desiree M
Assuntos: 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 ; Humans ; Jews - genetics ; Male ; Mice ; Models, Molecular ; Molecular Sequence Data ; Motor Neurons - cytology ; Motor Neurons - metabolism ; Mutant Proteins - genetics ; Mutant Proteins - metabolism ; Mutation ; Mutation - genetics ; Pathogenesis ; Pedigree ; Polypeptides ; Profilins - genetics ; Profilins - metabolism ; Protein Conformation ; Proteins ; Risk factors ; Ubiquitination
É parte de: Nature (London), 2012-08, Vol.488 (7412), p.499-503
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: London: Nature Publishing Group
Idioma: Inglês

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Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

London: Nature Publishing Group

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