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Title
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Hunting for novel frontotemporal dementia genes : challenges of gene identification in the era of next-generation sequencing
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Author
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Abstract
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| Frontotemporal dementia (FTD) is a leading cause of early-onset dementia (EOD). Like for other dementias, no effective treatments exist. The clinical and biological complexity of dementia has long been underestimated. To improve diagnosis and therapy development, we need a better understanding of the underlying disease causes, to which we aimed to contribute by studying the genetic etiology of FTD. Major insights into the pathological mechanisms underlying FTD have come from genetic studies, and have allowed identification of key genes and proteins in FTD. Nevertheless, half of the patients with a positive family history remain unexplained, suggesting underlying causes in other not yet identified genes. Despite availability of massive sequencing technologies, gene hunting remains challenging, particularly because of the difficulties in rare-variant interpretation (the so-called variants of uncertain significance, VUS). It is in this context that our research is situated, where we aimed to contribute to the further unravelling of the genetic etiology and molecular signatures of FTD, by family-based gene-hunting, validation of candidate genes in extended patient cohorts, and elucidation of the driving molecular mechanisms. One of these molecular mechanisms is the role of aberrant RNA-binding proteins (RBPs) in perturbing stress granule (SG) dynamics and seeding of toxic protein aggregation. Mutations in a growing number of RBP coding genes have been shown to interfere with SG formation, and cause or influence disease. We propose that aggregation-prone RBPs should be considered candidate genes, and offer opportunities for gene prioritization when mining sequencing data of unresolved FTD and related amyotrophic lateral sclerosis (ALS) patients. In line with this, we provide first genetic evidence for a causal implication of a novel RBP gene, RBM45, in the FTD-ALS spectrum. In a second family-based exome gene-hunting effort, we present two possible candidate genes that require further follow-up to demonstrate causality. Sharing these genetic findings, even though preliminary or affecting just a handful of patients, is of importance to move the field forward, as they may trigger replication studies and present converging evidence with other related research. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Biomedical Sciences
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2019
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Volume/pages
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169 p.
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Note
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van der Zee, Julie [Supervisor]
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Van Broeckhoven, Christine [Supervisor]
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