P3‐206: Genetic variability at the progranulin locus contributes to risk for Alzheimer's disease
Year: 2008
Type: article
Study design: Observational Study
Abstract: Null mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether genetic variability in PGRN contributes to Alzheimer disease (AD) in an extended Belgian AD patient group (N=779, onset age 74.7 ± 8.7 years). PGRN coding and regulatory regions were screened by direct sequencing. The effect of identified missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common variants were estimated by logistic regression analysis and haplotype analysis. We observed seven missense mutations in eight patients (1.3%). Also, missense mutations were three times more frequent in patients than in control individuals (2.0% vs. 0.7%). In silico predictions provided strong evidence for a pathogenic nature of at least two of these missense mutations. Molecular modeling showed a destabilizing effect on protein folding suggestive for loss of PGRN by degradation of the misfolded protein. Preliminary data suggest mutant PGRN exhibits reduced growth stimulatory activity in cultured cells compared to wild-type PGRN. Further, we showed that PGRN haplotypes were significantly associated with risk for AD. We provide evidence that genetic variations, missense mutations and common variants, in PGRN contribute to risk for AD. We hypothesize that missense mutations most probably lead to a partial loss of functional protein. Also, these missense mutations might lower the threshold for neurodegeneration and formation of pathologic lesions of AD.
Source: Alzheimer s & Dementia
Authors: Nathalie Brouwers, Kristel Sleegers, Sebastiaan Engelborghs, Sébastian Maurer-Stroh, Ilse Gijselinck, Julie van der Zee, Barbara Pickut, Marleen Van den Broeck, Maria Mattheijssens, Karin Peeters, Joost Schymkowitz, Frédéric Rousseau, Jean-Jacques Martin, Marc Cruts, Peter Paul De Deyn, Christine Van Broeckhoven
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2026401766