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Project

Onset age variability in GRN-associated frontotemporal lobar degeneration: identification of a functional onset age modifier.

Mutations in the granulin gene (GRN) are a major cause of frontotemporal lobar degeneration (FTLD). A striking feature of these patients is the wide onset age variability, which can span up to 40 years within one family. Identifying onset age modifiers is of importance as they might represent targets for disease-delaying therapies. Currently, there are no cures for FTLD patients. The modifiers could also be relevant in the context of disease prognosis and genetic counseling. We have used a family-based approach to identify onset age modifiers, starting from an extended Belgian founder family segregating a GRN mutation. Patients of the family have onset ages ranging from 45 to 80 years. In this family, we have identified a genomic locus that affects the onset age. This project aims to identify the functional onset age modifier gene and variant within this locus, and to extend the findings to international patient cohorts. We will perform a high-throughput screen to prioritize functional variants within the locus, expression analyses on brain material and lymphoblast cell lines, and cellular assays in induced pluripotent stem cell-derived cortical neurons of carriers of the GRN founder mutation to study the effect of candidate modifier genes and variants. We will investigate the modifier variant in extended international patient cohorts. Such a genetic epidemiological characterization will be relevant for possible applications in a clinical setting.
Date:1 Oct 2019 →  30 Sep 2023
Keywords:FRONTOTEMPORAL LOBAR DEGENERATION
Disciplines:Quantitative genetics, Molecular and cell biology not elsewhere classified, Genetics
Project type:Collaboration project