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Mouse models for Angelman syndrome: generation and characterization
Syding, Linn Amanda ; Sedláček, Radislav (advisor) ; Vyklický, Ladislav (referee) ; Valeš, Karel (referee)
Angelman syndrome (AS) is a neurodevelopmental disease found in 1 to 10,000 to 40,000 births, exhibiting an equal gender ratio. Key characteristics of the disease include an ataxic gait with tremor, severe mental retardation, profound speech impairment and seizures. Behavioral deficits such as increased anxiety and autism spectrum disorder features is found in affected individuals as well. The disease stems from the imprinted region 15q11.2-13q where genes are either maternally or paternally expressed as a result of parent-of-origin specific expression of the alleles. There are four main genetic etiologies causing AS namely, i) a large deletion ranging from 4-6 Mb on the maternally inherited allele including imprinted and bi-allelically expressed genes, ii) maternal deletion of the Ubitiquin ligase E3 (UBE3A) gene, iii) paternal uniparental disomy and iv) imprinting defect leading to inappropriate methylation of the locus. So far, there is no cure for AS rather the symptoms are ameliorated using a multidisciplinary approach. The goal of the doctoral study was to further decipher the role of Ube3a and Gabra5 using two mouse models to gain more knowledge about the involvement of these two genes for future therapeutic interventions in for Angelman syndrome. One model generated was a full gene deletion...
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Deciphering the biological role of Ddi1-like protein family
Sivá, Monika ; Grantz Šašková, Klára (advisor) ; Bařinka, Cyril (referee) ; Stopka, Pavel (referee)
Ddi1-like protein family has been recently raised into the spotlight by the scientific community due to its important roles in cellular homeostasis maintenance. It represents a specific group among shuttling proteins of the ubiquitin-proteasome system. When compared to other shuttles, Ddi1-like protein family members harbor a unique retroviral-protease like domain besides the conventional ubiquitin-like (UBL) domain and domains interacting with ubiquitin. In addition, a helical domain of Ddi (HDD) has been recently found in most of the orthologs. In this thesis, I focus on characterization of several members of Ddi1-like protein family, both on molecular level using NMR and in model mouse strains via a variety of biological methods. Solution structure of the UBL domain of Ddi1p of S. cerevisiae was solved and its characteristics were compared to those of the UBL domain of its human ortholog. Furthermore, we show that human DDI2 specifically binds to ubiquitin with its terminal domains, both the UBL and the UIM; however, with very low affinity in contrast to binding properties of its yeast counterpart. Our study also show that hDDI2 does not form a head-to-tail homodimer. Based on our structural studies, we hypothesize that human DDI2 might have evolved a different function compared to its yeast...
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Deciphering the biological role of Ddi1-like protein family
Sivá, Monika ; Grantz Šašková, Klára (advisor) ; Bařinka, Cyril (referee) ; Stopka, Pavel (referee)
Ddi1-like protein family has been recently raised into the spotlight by the scientific community due to its important roles in cellular homeostasis maintenance. It represents a specific group among shuttling proteins of the ubiquitin-proteasome system. When compared to other shuttles, Ddi1-like protein family members harbor a unique retroviral-protease like domain besides the conventional ubiquitin-like (UBL) domain and domains interacting with ubiquitin. In addition, a helical domain of Ddi (HDD) has been recently found in most of the orthologs. In this thesis, I focus on characterization of several members of Ddi1-like protein family, both on molecular level using NMR and in model mouse strains via a variety of biological methods. Solution structure of the UBL domain of Ddi1p of S. cerevisiae was solved and its characteristics were compared to those of the UBL domain of its human ortholog. Furthermore, we show that human DDI2 specifically binds to ubiquitin with its terminal domains, both the UBL and the UIM; however, with very low affinity in contrast to binding properties of its yeast counterpart. Our study also show that hDDI2 does not form a head-to-tail homodimer. Based on our structural studies, we hypothesize that human DDI2 might have evolved a different function compared to its yeast...
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Developmental specifics of individuals with Angelman syndrome and Prader - Willi syndrome as the basis for special educator's work
Doubková, Světla ; Šumníková, Pavlína (advisor) ; Durdilová, Lucie (referee)
Developmental specifics of individuals with Angelman and Prader - Willi syndrome as the basis for special educator's work The thesis deals in a complex way with the issue of two rare syndromes - Angelman and Prader- Willi syndrome. It describes the manifestations and genetic background, outlines the options for special education and rehabilitation interventions as well as selected medical and regime measures. The thesis informs about the category of rare diseases and also mentions the strategies for approach to these diseases used in the Czech Republic. It also comprises a list of organizations in the Czech Republic that deal with the Angelman and Prader - Willi syndrome and which associate parents and others interested in this topic. The end, the thesis comprises casuistry of two individuals, characteristic syndrome bearers, and conclusions of a questionnaire survey among parents. Surveys through questionnaires illustrate the specific characteristics of inidividuals that have been used to define areas of support. The goal of the thesis was to describe the possibilities for pedagogic and other interdisciplinary interventions, map the situation in the Czech Republic, and to provide more information about this issue to anyone interested.
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Angelmanův syndrom - etiologie a klinický obraz onemocnění
HOLEČKOVÁ, Karolína
Angelman syndrome (Happy puppet syndrome) is a rare genetic disease. It is a microdeletion syndrome, mostly caused by maternal deletion of chromosome 15q11-q13, or by paternal uniparental disomy of chromosome 15, or by other mutation (for example mutations in UBE3A gene). Angelman syndrome was first described in 1965 by Harry Angelman, an English pediatrician. It is estimated that this disease occurs in 1 in 10 000 to 1 in 30 000 individuals. The syndrome is characterised by severe mental retardation, underdeveloped speech or absent (rather nonverbal expression is used), motor skills problems (stiff walk, jerky movements, reminiscent of puppet), happy mood and unreasonable fits of laughter. There are epileptic seizures, attention deficit disorder, abnormal EEG, hypotonia or microcephaly in approximately 80 % of cases.
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