Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
dc.contributor.author | Wu, Chi-Hong | |
dc.contributor.author | Keagle, Pamela J. | |
dc.contributor.author | Sapp, Peter | |
dc.contributor.author | Piotrowska, Katarzyna | |
dc.contributor.author | Lowe, Patrick | |
dc.contributor.author | McKenna-Yasek, Diane | |
dc.contributor.author | Baron, Desiree | |
dc.contributor.author | Kost, Jason E. | |
dc.contributor.author | Gonzalez-Perez, Paloma | |
dc.contributor.author | Fox, Andrew D. | |
dc.contributor.author | Adams, Jenni | |
dc.contributor.author | Leclerc, Ashley Lyn | |
dc.contributor.author | Moore, Melissa J. | |
dc.contributor.author | Zitzewitz, Jill A. | |
dc.contributor.author | Xu, Zuoshang | |
dc.contributor.author | Bosco, Daryl | |
dc.contributor.author | Brown, Robert H. Jr. | |
dc.contributor.author | Landers, John E. | |
dc.date | 2022-08-11T08:08:56.000 | |
dc.date.accessioned | 2022-08-23T16:12:45Z | |
dc.date.available | 2022-08-23T16:12:45Z | |
dc.date.issued | 2012-08-23 | |
dc.date.submitted | 2016-06-20 | |
dc.identifier.citation | Nature. 2012 Aug 23;488(7412):499-503. doi: 10.1038/nature11280. <a href="http://dx.doi.org/10.1038/nature11280">Link to article on publisher's site</a> | |
dc.identifier.issn | 0028-0836 (Linking) | |
dc.identifier.doi | 10.1038/nature11280 | |
dc.identifier.pmid | 22801503 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/33463 | |
dc.description | <p>Full author list omitted for brevity. For the full list of authors, see article.</p> | |
dc.description.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. | |
dc.language.iso | en_US | |
dc.relation | <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=22801503&dopt=Abstract">Link to Article in PubMed</a> | |
dc.relation.url | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575525/ | |
dc.subject | Genetics | |
dc.subject | Genomics | |
dc.subject | Molecular Biology | |
dc.subject | Molecular Genetics | |
dc.subject | Nervous System Diseases | |
dc.subject | Neurology | |
dc.subject | Neuroscience and Neurobiology | |
dc.title | Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis | |
dc.type | Journal Article | |
dc.source.journaltitle | Nature | |
dc.source.volume | 488 | |
dc.source.issue | 7412 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/gsbs_sp/1992 | |
dc.identifier.contextkey | 8749589 | |
html.description.abstract | <p>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.</p> | |
dc.identifier.submissionpath | gsbs_sp/1992 | |
dc.contributor.department | Department of Biochemistry and Molecular Pharmacology | |
dc.contributor.department | Department of Neurology | |
dc.source.pages | 499-503 | |
dc.contributor.student | Chi-Hong Wu |