Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
Keagle, Pamela J.
Kost, Jason E.
Fox, Andrew D.
Leclerc, Ashley Lyn
Moore, Melissa J.
Zitzewitz, Jill A.
Brown, Robert H. Jr.
Landers, John E.
Student AuthorsChi-Hong Wu
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Department of Neurology
Document TypeJournal Article
Nervous System Diseases
Neuroscience and Neurobiology
MetadataShow full item record
AbstractAmyotrophic 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.
SourceNature. 2012 Aug 23;488(7412):499-503. doi: 10.1038/nature11280. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33463
Full author list omitted for brevity. For the full list of authors, see article.
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