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Project

Understanding reduced penetrance of ABCA7 premature termination codon mutations in Alzheimer's disease.

Evidence accumulates that predicted loss-of-function mutations in the Alzheimer risk gene ABCA7 are 4 — 5 times more frequent among Alzheimer's disease (AD) patients than cognitively healthy individuals. Two striking characteristics of ABCA7 mutation carriers are -on the one hand- an increased proportion of familial disease, and -on the other hand- wide spread in onset age and incomplete penetrance. Thus, while these mutations might be clinically relevant given their relatively high frequency and significant effect on personal as well as familial disease risk, reduced penetrance currently hinders implementation of genetic screening for ABCA7 mutations in clinical practice. In a pilot experiment using third generation cDNA sequencing, we identified potential rescue mechanisms at transcript level that may explain reduced penetrance of these mutations. Here, we propose to perform long-read cDNA sequencing analyses on different tissues of a large series of mutation carriers, and correlate mutation-rescue events with parameters of disease severity. We have an unprecedented repository containing 104 ABCA7 PTC mutation carriers, putting us in a unique position to conduct this project. The outcomes of this project will be important for informed decision making on diagnostic screening of ABCA7 in AD. The insights gained through nature's own rescue experiments at transcript level will provide a window onto pharmaceutical intervention strategies for this genetic subtype of AD.
Date:1 Jan 2018 →  31 Dec 2021
Keywords:ALZHEIMER'S DISEASE
Disciplines:Genetics, Systems biology, Molecular and cell biology