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dc.contributor.authorWilliams, Kelly L.
dc.contributor.authorKost, Jason
dc.contributor.authorBrown, Robert H. Jr.
dc.contributor.authorLanders, John E
dc.contributor.authorBlair, Ian P.
dc.date2022-08-11T08:09:45.000
dc.date.accessioned2022-08-23T16:42:16Z
dc.date.available2022-08-23T16:42:16Z
dc.date.issued2016-04-15
dc.date.submitted2016-10-05
dc.identifier.citationNat Commun. 2016 Apr 15;7:11253. doi: 10.1038/ncomms11253. <a href="http://dx.doi.org/10.1038/ncomms11253">Link to article on publisher's site</a>
dc.identifier.issn2041-1723 (Linking)
dc.identifier.doi10.1038/ncomms11253
dc.identifier.pmid27080313
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40057
dc.description<p>Full author list omitted for brevity. For full list of authors see article.</p>
dc.description.abstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27080313&dopt=Abstract">Link to Article in PubMed</a>
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectComputational Biology
dc.subjectGenomics
dc.subjectMolecular and Cellular Neuroscience
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.titleCCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
dc.typeJournal Article
dc.source.journaltitleNature communications
dc.source.volume7
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3866&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2861
dc.identifier.contextkey9233080
refterms.dateFOA2022-08-23T16:42:16Z
html.description.abstract<p>Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.</p>
dc.identifier.submissionpathoapubs/2861
dc.contributor.departmentDepartment of Neurology
dc.source.pages11253


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