From G-secretase in APO-SUS/-UNSUS rats to translational research in complex human disorders
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Publication year
2009Author(s)
Publisher
S.l : [S.n.]
ISBN
9789090236858
Number of pages
223 p.
Annotation
Radboud Universiteit Nijmegen, 09 januari 2009
Promotor : Martens, G.J.M.
Publication type
Dissertation

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Organization
Molecular Animal Physiology
Former Organization
Molecular Animal Physiology
Subject
Molecular Animal PhysiologyAbstract
Nearly all diseases have a genetic component, with some caused by alterations in a single gene (monogenic diseases). For most diseases, however, the causes are much more complex since they are thought to result from an interaction between (more than one) genetic variation and environmental factors. Due to these complex interactions, the causative genes that contribute to the complex disorders are elusive. The objective of this thesis was to provide a contribution to a better understanding of the genes and pathways involved in complex disorders. We used pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) that display a number of behavioural features as seen in complex disorders in human. Microarray analyses revealed a reduced expression of the -secretase component Aph-1b in APO-SUS rats, relative to their phenotypic counterpart APO-UNSUS rats. Genomic analysis of the Aph-1b locus revealed a gene-dosage imbalance that segregated with various behavioural traits. In addition, we discovered additional (epi)genetic variations between the two rat lines, including eight copy number variations, two genetic variants corresponding to topoisomerase II-based recombination hot spots and one epigenetic variation (DNA methylation). Together, these findings suggest that the genetic and epigenetic variations contribute to the complex APO-SUS phenotype. On the basis of the results obtained with the APO-SUS/-UNSUS rats, we performed human association studies to examine whether Aph-1b is involved in the pathogenesis of disorders with a complex aetiology. We found that a single-nucleotide polymorphism in the human Aph-1b gene affected -secretase cleavage and was associated with a number of complex diseases, including atherosclerosis, epileptic seizures, HIV-1 infection and colorectal cancer. Thus, alterations in -secretase cleavage activity may contribute to the pathogenesis of a number of complex traits and disorders.
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- Academic publications [202863]
- Dissertations [12257]
- Electronic publications [101064]
- Faculty of Science [31874]
- Open Access publications [69739]
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