title: Contribution of TARDBP to Alzheimer's disease genetic etiology.
abstract: 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.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Karolien
authors.initials: K
authors.lastname: Bettens
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Pickut
authors.forename: Helen
authors.initials: H
authors.lastname: Van Miegroet
authors.forename: Ana Gil
authors.initials: AG
authors.lastname: Montoya
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D004268:DNA-Binding Proteins; D019913:Nuclear Localization Signals