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Title
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Contribution of rare genetic variants to the complex etiology of neurodegenerative brain diseases
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Author
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Abstract
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| One of the major attempts of medical research is to entirely comprehend the neurodegenerative brain diseases (NBDs) etiology. These widespread disorders have an enormous impact on patients and families. Available therapeutic strategies are only able to attenuate symptoms. Neurodegeneration in the brain therefore progresses towards an irremediable loss of neurons. The patients’ condition severely worsening to a state of incapability to perform everyday life activities. The most common disease NBDs subtypes are Alzheimer’s disease (AD) and Parkinson’s disease, followed by less frequent known as frontotemporal dementia and Amyotrophic Lateral Sclerosis. The past three decades have witnessed major advances in understanding NBDs molecular etiology. Initial genetic and association studies on affected individuals have discovered causal and risk genes underlying the biological mechanisms of neurodegeneration. Unfortunately, these mutated genes could only explain a small proportion of the affected patients. After whole exome and genome sequencing tools became available, an unprecedented rate of novel NBDs genes has been discovered. A large number of rare variants has therefore been identified of which contribution to disease remains still unclear. To date, functional research aiming to demonstrate the effect of genetic mutations on the protein function is scarce and these variants of uncertain significance (VUS) remain uncharacterized. This leaves a large fraction of the genetic NBDs etiology unexplained. The work performed during this PhD aimed to clarify whether rare variants in NBD genes, identified through next generation sequencing, contribute to the disease etiology. To achieve this, the main NBD disease genes were screened in Belgian early-onset dementia patients with unclear clinical symptoms. A more accurate diagnosis was given to patients with a known pathogenic mutation identified. VUS were also observed, two of which were further characterized using patient biomaterials. Results from this study highlighted the NBDs genetic heterogeneity and corroborated the hypothesis of an NBDs disease continuum, further supported by the screening of two recently identified ALS genes (TUBA4A, CHCHD10) in Belgian FTD-ALS patients. Finally, the established AD disease genes (APP, PSEN1, PSEN2) were screened in Belgian AD patients. Both known pathogenic mutations and VUS were discovered. Cerebral spinal fluid was available for a subset of mutation carriers to further investigate a possible pathogenic role for amyloid-? 43 peptide in AD pathogenesis, which has recently raised attention in this field. The work performed during this PhD has provided evidence for the importance of deciphering the possible pathogenic effect of the VUS in the NBDs. |
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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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144 p.
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