| TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. | |
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MedLine Citation:
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PMID: 19618195 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3'-untranslated region (3'-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3'-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy. |
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Authors:
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Michael A Gitcho; Eileen H Bigio; Manjari Mishra; Nancy Johnson; Sandra Weintraub; Marsel Mesulam; Rosa Rademakers; Sumi Chakraverty; Carlos Cruchaga; John C Morris; Alison M Goate; Nigel J Cairns |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-07-18 |
Journal Detail:
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Title: Acta neuropathologica Volume: 118 ISSN: 1432-0533 ISO Abbreviation: Acta Neuropathol. Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-02 Completed Date: 2010-02-25 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0412041 Medline TA: Acta Neuropathol Country: Germany |
Other Details:
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Languages: eng Pagination: 633-45 Citation Subset: IM |
Affiliation:
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Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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3' Untranslated Regions
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genetics* Aged Aged, 80 and over Amyotrophic Lateral Sclerosis / genetics, metabolism, pathology Autopsy / methods Brain / metabolism, pathology Chi-Square Distribution DNA Mutational Analysis / methods DNA-Binding Proteins / genetics*, metabolism* Female Frontotemporal Lobar Degeneration* / genetics, metabolism, pathology Genetic Predisposition to Disease* Genetic Variation / genetics* Humans Male Middle Aged RNA, Messenger / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P01 AG003991-25/AG/NIA NIH HHS; P01-AG03991/AG/NIA NIH HHS; P30 AG013854-09/AG/NIA NIH HHS; P30 AG013854-149003/AG/NIA NIH HHS; P30-AG13854/AG/NIA NIH HHS; P30-NS057105/NS/NINDS NIH HHS; P50 AG005681-26/AG/NIA NIH HHS; P50 AG016574-11/AG/NIA NIH HHS; P50 AG16574/AG/NIA NIH HHS; P50-AG05681/AG/NIA NIH HHS; U01 AG016976-03/AG/NIA NIH HHS; U01-AG16976/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/3' Untranslated Regions; 0/DNA-Binding Proteins; 0/RNA, Messenger; 0/protein TDP-43 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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