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dc.contributor.authorWu, Chi-Hong
dc.contributor.authorKeagle, Pamela J.
dc.contributor.authorSapp, Peter
dc.contributor.authorPiotrowska, Katarzyna
dc.contributor.authorLowe, Patrick
dc.contributor.authorMcKenna-Yasek, Diane
dc.contributor.authorBaron, Desiree
dc.contributor.authorKost, Jason E.
dc.contributor.authorGonzalez-Perez, Paloma
dc.contributor.authorFox, Andrew D.
dc.contributor.authorAdams, Jenni
dc.contributor.authorLeclerc, Ashley Lyn
dc.contributor.authorMoore, Melissa J.
dc.contributor.authorZitzewitz, Jill A.
dc.contributor.authorXu, Zuoshang
dc.contributor.authorBosco, Daryl A
dc.contributor.authorBrown, Robert H. Jr.
dc.contributor.authorLanders, John E
dc.date2022-08-11T08:08:56.000
dc.date.accessioned2022-08-23T16:12:45Z
dc.date.available2022-08-23T16:12:45Z
dc.date.issued2012-08-23
dc.date.submitted2016-06-20
dc.identifier.citationNature. 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.issn0028-0836 (Linking)
dc.identifier.doi10.1038/nature11280
dc.identifier.pmid22801503
dc.identifier.urihttp://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.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.
dc.language.isoen_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.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575525/
dc.subjectGenetics
dc.subjectGenomics
dc.subjectMolecular Biology
dc.subjectMolecular Genetics
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.subjectNeuroscience and Neurobiology
dc.titleMutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
dc.typeJournal Article
dc.source.journaltitleNature
dc.source.volume488
dc.source.issue7412
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/1992
dc.identifier.contextkey8749589
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.submissionpathgsbs_sp/1992
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentDepartment of Neurology
dc.source.pages499-503
dc.contributor.studentChi-Hong Wu


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