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Determination of mutation spectrum and frequency representation of variants in genes involved in Melanocortin Receptor Type 4 Signaling Cascade (MC4R)
Toman, Izabela ; Včelák, Josef (advisor) ; Aldhoon Hainerová, Irena (referee)
This master's thesis is focused on determination of mutation spectrum and frequency representation of variants in genes involved in Melanocortin Receptor Type 4 Signaling Cascade. Mutation in genes connected to MC4R signalisation cascade may induce so called monogenic type of obesity, which is characterised not only by mutation in single gene but also by an early onset severe obesity and hyperphagia. Due to new means of medications being introduced its especially important to ascertain the frequency of mutations in Czech children and adolescent population. Theoretic part of the thesis is devoted to description of energy homestasis and leptin- melanocortin pathway. Physiology of hunger and satiety and the most common causes of obesity and monogenic obesity are also included. There is also mention of population differences in genetical predisposition for monogenic obesity namely in genes MC4R, POMC, SIM1 and BDNF which were the focal points of this thesis. In practical part, genetical analysis of 1910 samples from Czech children and adolescent population was implemented. We identified twelve different, likely pathogenic causal variants via next generation sequencing. More precisely eight different MC4R variants, 2 POMC variants and 2 SIM1 variants. In those, two novel variants were found c.346 C> T...
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Monogenic causes of obesity
Toman, Izabela ; Včelák, Josef (advisor) ; Vaňková, Markéta (referee)
In recent years the prevalence of obesity has significantly increased, pursued by multiplication of patients with type 2 diabetes, cardiological problems and premature death. Between the most dangerous forms of obesity belongs its monogenic type as it is a disease caused by single causal mutation with typical phenotype of severe obesity and hyperphagia. The aspiration of this thesis is to summarise the most important genes, mutation of which may cause monogenic type of obesity. The first chapters outline general genetic causes of obesity and importance of Leptin-melanocortin pathway in terms of its role in energy homeostasis. Subsequent sections identify genes involved in monogenic obesity, e.g. MC4R, LEP, LEPR, SIM1 and BDNF. Finally, the thesis summarizes possible new treatments, including new drug "Setmelanotide". Key words: Genetics, Obesity, Monogenic obesity, Leptin-Melanocortin pathway, MC4R, Setmelanotide
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