Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
Authors
Wu, Chi-HongKeagle, Pamela J.
Sapp, Peter
Piotrowska, Katarzyna
Lowe, Patrick
McKenna-Yasek, Diane
Baron, Desiree
Kost, Jason E.
Gonzalez-Perez, Paloma
Fox, Andrew D.
Adams, Jenni
Leclerc, Ashley Lyn
Moore, Melissa J.
Zitzewitz, Jill A.
Xu, Zuoshang
Bosco, Daryl
Brown, Robert H. Jr.
Landers, John E.
Student Authors
Chi-Hong WuUMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDepartment of Neurology
Document Type
Journal ArticlePublication Date
2012-08-23Keywords
GeneticsGenomics
Molecular Biology
Molecular Genetics
Nervous System Diseases
Neurology
Neuroscience and Neurobiology
Metadata
Show full item recordAbstract
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.Source
Nature. 2012 Aug 23;488(7412):499-503. doi: 10.1038/nature11280. Link to article on publisher's siteDOI
10.1038/nature11280Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33463PubMed ID
22801503Notes
Full author list omitted for brevity. For the full list of authors, see article.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/nature11280