Angelman Syndrome (AS) is a severe neurodevelopmental disorder, caused by the neuronal absence of the ubiquitin protein ligase E3A (UBE3A). UBE3A promotes ubiquitin-mediated protein degradation and... Show moreAngelman Syndrome (AS) is a severe neurodevelopmental disorder, caused by the neuronal absence of the ubiquitin protein ligase E3A (UBE3A). UBE3A promotes ubiquitin-mediated protein degradation and functions as a transcriptional coregulator of nuclear hormone receptors, including the glucocorticoid receptor (GR). Previous studies showed anxiety-like behavior and hippocampal-dependent memory disturbances in AS mouse models. Hippocampal GR is an important regulator of the stress response and memory formation, and we therefore investigated whether the absence of UBE3A in AS mice disrupted GR signaling in the hippocampus. We first established a strong cortisol-dependent interaction between the GR ligand binding domain and a UBE3A nuclear receptor box in a high-throughput interaction screen. In vivo, we found that UBE3A-deficient AS mice displayed significantly more variation in circulating corticosterone levels throughout the day compared to wildtypes (WT), with low to undetectable levels of corticosterone at the trough of the circadian cycle. Additionally, we observed an enhanced transcriptomic response in the AS hippocampus following acute corticosterone treatment. Surprisingly, chronic corticosterone treatment showed less contrast between AS and WT mice in the hippocampus and liver transcriptomic responses. This suggests that UBE3A limits the acute stimulation of GR signaling, likely as a member of the GR transcriptional complex. Altogether, these data indicate that AS mice are more sensitive to acute glucocorticoid exposure in the brain compared to WT mice. This suggests that stress responsiveness is altered in AS which could lead to anxiety symptoms. Show less
Aim of the dissertation: To expand the knowledge on the behavioural phenotypes, level of parenting stress and the relationship between child characteristics and parenting stress in five genetic... Show moreAim of the dissertation: To expand the knowledge on the behavioural phenotypes, level of parenting stress and the relationship between child characteristics and parenting stress in five genetic syndromes. The included syndromes are Angelman, CHARGE, Cornelia de Lange, Prader-Willi, and Rett syndrome. All syndromes are associated with intellectual disabilities. Method: Participants were children and adults with one of the syndromes and their parents, recruited through the Dutch Parent Support Groups. Parents filled out questionnaires concerning parenting stress and behavioural characteristics of their child. Additionally an interview regarding autistic traits of the child was administrated with parents. Main results: The behavioural phenotypes of the syndromes are described in detail. In all syndromes there is a high risk to display autistic traits. The syndromes can been seen as a risk factor for high levels of parenting stress. Specialized psycho-education on the behavioural strengths and weaknesses of a specific syndrome should be given to parents. Awareness on the high prevalence of autistic traits is important to be able to shape an optimum adaptive environment. Professionals should not only focus on the child with the syndrome, but also on the family system given the high stress levels for parents. Show less
