Contribution of TARDBP to Alzheimer's Disease Genetic Etiology

Article type: Research Article

Authors: Brouwers, Nathalie^{a; b; c} | Bettens, Karolien^{a; b; c} | Gijselinck, Ilse^{a; b; c} | Engelborghs, Sebastiaan^{c; d; e} | Pickut, Barbara A.^e | Van Miegroet, Helen^{a; b; c} | Montoya, Ana Gil^{a; b; c} | Mattheijssens, Maria^{a; b; c} | Peeters, Karin^{a; b; c} | De Deyn, Peter P.^{c; d; e} | Cruts, Marc^{a; b; c} | Sleegers, Kristel^{a; b; c} | Van Broeckhoven, Christine^{a; b; c; *}

Affiliations: [a] Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium | [b] Laboratory of Neurogenetics, Institute Born-Bunge, Antwerpen, Belgium | [c] University of Antwerp, Antwerpen, Belgium | [d] Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Antwerpen, Belgium | [e] Memory Clinic and Division of Neurology, ZNA Middelheim; Antwerpen, Belgium

Correspondence: [*] Correspondence to: Prof. Dr. Christine Van Broeckhoven, PhD DSc, Neurodegenerative Brain Diseases Group, VIB -- Department of Molecular Genetics, University of Antwerp -- Campus CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium. Tel.: +32 3 265 1001; Fax: +32 3 265 1012; E-mail: [email protected].

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.

Keywords: Alzheimer's disease, association analysis, genetics, mutation analysis, TARDBP

DOI: 10.3233/JAD-2010-100198

Journal: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 423-430, 2010