Contribition of TARDBP to Alzheimer's disease genetic etiology
| Autor: | Ilse Gijselinck, Christine Van Broeckhoven, Karolien Bettens, Helen Van Miegroet, Karin Peeters, Kristel Sleegers, Nathalie Brouwers, Ana Gil Montoya, Peter Paul De Deyn, Maria Mattheijssens, Sebastiaan Engelborghs, Barbara A. Pickut, Marc Cruts |
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| Přispěvatelé: | Clinical sciences, Neurology |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male DNA Mutational Analysis Nuclear Localization Signals Single-nucleotide polymorphism Biology TARDBP Polymorphism Single Nucleotide Exon Alzheimer Disease Exons/genetics mental disorders medicine Missense mutation Humans Point Mutation Age of Onset Alzheimer Disease/etiology Genetic association Aged Medicine(all) Genetics Aged 80 and over General Neuroscience Point mutation Haplotype Genetic Variation General Medicine Frontotemporal lobar degeneration Exons Middle Aged medicine.disease Nuclear Localization Signals/genetics DNA-Binding Proteins Psychiatry and Mental health Clinical Psychology Female Human medicine Geriatrics and Gerontology DNA-Binding Proteins/genetics |
| Zdroj: | Journal of Alzheimer's disease |
| ISSN: | 1387-2877 |
| Popis: | The nuclear transactive response (TAR) DNA binding protein-43, TDP-43, is a major constituent of the ubiquitinated neuronal inclusions in patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Missense mutations in TDP-43 have been associated with familial and sporadic ALS. Since TDP-43 immunoreactivity was also frequently observed in Alzheimer's disease (AD) brains and elevated TDP-43 plasma levels were detected in a subset of AD patients, we sequenced the TDP-43 gene, TARDBP, in a well-documented group of AD patients (n=485). We observed one mutation in exon 3 (c.269C>T) predicting a p.Ala90Val substitution in two patients. One extra p.Ala90Val carrier was observed by sequencing exon 3 of an additional set of 254 AD patients. The mutation was absent from 604 control individuals. Allele and haplotype analysis using microsatellite markers suggested that the three patients might share a common founder. However, co-segregation of p.Ala90Val with AD could not be realized leaving its pathogenic unclear at this moment. Also, sequencing in 190 additional AD patients of TARDBP exon 6 in which pathogenic mutations have been reported in FTLD and ALS was negative. Further, genetic association analyses using five single nucleotide polymorphisms did not detect significant differences between AD patients and control individuals. In conclusion, the genetic contribution of TARDBP to AD was restricted to the rare mutation p.Ala90Val (3/739, 0.4%) of unclear pathogenic nature that affects the nuclear localization signal in TDP-43. |
| Databáze: | OpenAIRE |
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