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The influence of gene polymorphisms on the progression of renal insufficiency
Maixnerová, Dita ; Merta, Miroslav (advisor) ; Kohoutová, Milada (referee) ; Nečas, Emanuel (referee)
I worked on the referred to dissertation thesis in the Department of Biology and Human Genetics in cooperation with the Department of Nephrology of General Teaching Hospital and the First School of Medicine at Charles University. I concentrated on the possible influence of gene polymorphisms on the progression of renal insufficiency of IgAN and ADPKD to ESRD. I investigated the gene polymorphisms of Endothelin and Megsin myself and I participated in examinations of other gene polymorphisms. In our study we were concerned with the gene polymorphisms of G198T, T-1370G a 3A/4A ET-1 and we did not find any differences by comparing genotype frequencies among the IgAN groups with normal renal function and ESRD. The haplotype analysis demonstrated the negative influence of GG4A haplotype (defined as G-198, G-1370 and 4 A allele). The association of GG4A haplotype with the progression of chronic glomerulonephritides, especially IgAN, might be explained by shared interaction of all ET-1 polymorphisms. Then we dealt with the research of C2093T, C2180T Megsin gene polymorphisms on the progression of IgAN in Czech patients. No obvious effect of these polymorphisms was found in single-gene or in haplotype analysis. Nevertheless, the Megsin haplotype reconstruction revealed that the TT haplotype (defined as T-2093,...
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Clinical and genetic characteristic of selected types of monogenic diabetes mellitus
Gonsorčíková, Lucie ; Lebl, Jan (advisor) ; Pelikánová, Terezie (referee) ; Kohoutová, Milada (referee)
1. English Summary The aim of this thesis was to find out the etiology of diabetes mellitus in patients with a family predisposition to the disease. The world-wide increase in the incidence of diabetes in the past years has lead to intensive research of its etiological and pathophysiological mechanisms. This research has helped to discover many genes whose mutations were proved to cause diabetes without a contribution of other factors. Such cases where a mutation in a single gene crucial for glucose control is sufficient to result in diabetes are referred to as monogenic diabetes. This group includes a broad spectrum of hyperglycaemic conditions that differ significantly in their prevalence, course, treatment as well as prognosis. The so called MODY (maturity onset diabetes of the young) belongs to this group and is characterized by early onset before 25 years of age and no need of insulin substitution initially. In this study we were looking for mutations in genes that may be a rare cause of monogenic diabetes. We examined patients with hyperglycaemia occurring in several generations of their families and in whom mutations in more prevalent MODY genes had been previously excluded. We performed a genetic analysis of genes NEUROD1, IPF-1 and ABCC8. The protein NEUROD1 is a crucial transcription factor that...
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Role some genetic factors in bodyweight changes
Aldhoon, Bashar ; Hainer, Vojtěch (advisor) ; Kohoutová, Milada (referee) ; Vašků, Anna (referee)
The aim of the study was to determine the role of certain genetic factors on the ability to maintain weight loss, as well as to reduce the health risks associated with obesity in a group of about 300 obese patients followed for 2.5 years. The first part dealt with monitoring the impact of P73T polymorphism of the neuromedin gene on body weight reduction and its relation to certain metabolic and psychobehavioral factors. In the group of obese men, T allele non-carriers achieved significant reduction in waist circumference at the end of the follow-up. This waist circumference reduction was accompanied by a significant reduction in energy intake and by a significant decrease in the Beck depression score, while dietary restraint score increased. In the group of obese women, no significant differences between carriers and non-carriers of the T allele were observed. The significant reduction in total energy intake and macronutrient consumption was achieved in obese women regardless the genotype. In the second part, the effect of the Leu162Val of PPAR and Pro12Ala of PPAR gene polymorphisms on body weight reduction and on metabolic and psychobehavioral factors was studied in a group of 246 obese women. At baseline, non-carriers compared to carriers of the minor Val-allele of PPAR gene exhibitied a favorable effect...
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Effect of gene expression in hyperproliterative skin diseases
Lysá, Barbora ; Arenberger, Petr (advisor) ; Kohoutová, Milada (referee) ; Brdička, Radim (referee) ; Nečas, Emanuel (referee)
The introductory part of this thesis gives insight into selected aspects of the issue deals with hyperproliferative outlining the molecular basis of skin diseases, which are included in addition to psoriasis as well as the characteristic representative of non-melanoma skin cancers. Further analyzes partly exogenous influence of UV radiation on their formation. The actual research work is focused on a group of genes whose expression was studied in actinic keratosis disease in relation to its treatment of topical immunomodulators - imiquimod. Examined genes can be divided into groups of genes modulating the immune response, genes involved in apoptotic processes and the genes playing a potential role in tumor formation.
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Molecular genetic analysis of the causes of selected hereditary forms of colorectal polyposis
Florianová, Martina ; Kohoutová, Milada (advisor) ; Křepelová, Anna (referee) ; Vodičková, Ludmila (referee)
Colorectal cancer (CRC) is one of the most common cancers worldwide. Hereditary colorectal adenomatous polyposis syndromes are a predisposition to colorectal carcinoma development. The most common analyzed syndromes are familial adenomatous polyposis (FAP) that results from germline mutations in the APC gene and MUTYH - associated polyposis (MAP) caused by germline mutations in the MUTYH gene. The aim of this study was to clarify genetics causes of colorectal polyposis in a set of probands without the germline mutation in the APC gene. Within studyʼs scope the presence of large deletion in APC gene was tested, there was looked for germline mutations in MUTYH gene, alternatively germline mutations in MSH6 gene by probands with monoallelic MUTYH mutation, item there was tested an effect of detected APC variants on gene expression. Screening for large deletions was performed by multiplex ligation dependent probe amplification (MLPA). A set of 120 APC-negative probands was examined for the presence of germline MUTYH mutations by denaturing high performance liquid chromatography (dHPLC). Subsequently a set of 145 APC-negative probands was screened only for germline MUTYH mutation in exon 7 and 13 by high resolution melting (HRM) analysis. Analysis of the effect on expression was tested by ten APC...
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Diagnosis of hypertrophic cardiomyopathy with emphasis on genetic testing
Tomašov, Pavol ; Veselka, Josef (advisor) ; Kohoutová, Milada (referee) ; Krejčí, Jan (referee)
Dizertační práce: Diagnostika hypertrofické kardiomyopatie se zaměřením na genetické vyšetření Autor: MUDr. Pavol Tomašov Obor: Fyziologie a patofyziologie člověka Abstract Introduction: Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with vast genetic and clinical heterogeneity. Genetic testing of HCM patients is important in determining the etiopathogenesis of the disease and is becoming an integral part of patient care. Aim: The aims of our work included the following implementation of genetic testing in HCM in both basic and clinical research: 1. To identify genetic variants in a novel candidate gene NEBL coding Z-disc protein nebulette in HCM patients. 2. To determine clinical and echocardiographic variables associated with the presence of mutations in the most common sarcomeric genes in the Czech population. 3. To find echocardiographic parameters useful in determining the genotype of relatives before the development of phenotype. Results: In a cohort of 95 patients with HCM we identified a novel genetic variant in a conserved spot of NEBL gene (p.H171R) in one patient. The variant was not found in a control population and was predicted to have a damaging effect on the protein's structure. In a cohort of 48 HCM patients tested for mutations in the most common sarcomeric...
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Molecular mechanisms of Wnt signalling in mammalian cells
Lukáš, Jan ; Kořínek, Vladimír (advisor) ; Kohoutová, Milada (referee) ; Macůrková, Marie (referee)
Wnt signalling represents an important mechanism participating in control of cellular and developmental processes, including establishment of cell polarity, cell fate specification, stem cell self-renewal, tissue patterning and organogenesis, homeostasis maintenance and regeneration. Misregulation of the Wnt signalling during embryogenesis leads to developmental defects while aberrant activation later in development is associated with degenerative diseases and a number of cancers. The presented PhD thesis is based on four original publications that deal with the post-translational modifications of Wnt ligands and molecular mechanisms contributing to the regulation of a transcriptional profile of the so-called canonical Wnt pathway. Wnt signalling pathway is used repetitively both in time and different cellular contexts throughout development of multicellular organisms. Inevitably, in each single situation -catenin/TCF complexes, the downstream effectors, induce only subsets of all potential target genes. How this differential tissue- and stage-specific control over various subsets of target genes is achieved with such a limited number of nuclear effectors is not fully understood. Along with the expression of specific LEF/TCF family members or their variants containing different functional domains...
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The influence of variants in genes associated with carcinogenesis on predisposition to and phenotype of hereditary and sporadic tumour diseases of gastrointestinal tract
Vasovčák, Peter ; Křepelová, Anna (advisor) ; Kohoutová, Milada (referee) ; Plevová, Pavlína (referee)
This PhD. thesis deals with four different topics for which an increased risk of the development of colorectal cancer (CRC) is the common denominator. The first part is aimed to Cowden syndrome (CS), the second to Peutz-Jeghers syndrome (PJS), the third to sporadic CRCs in Czech population and the fourth is dedicated to a patient with a constitutional mismatch repair deficiency syndrome (CMMR-D) and a particular mutational profile. Cowden syndrome (CS) is an autosomal dominant disorder with a predisposition to tumours, especially breast, thyroid and uterine tumours. Pathognomonic features are mucocutaneous lesions with almost a 100% penetrance until 30 years of age (1). Despite the established diagnostic criteria (2), classification of the CS is a challenge due to extremely variable phenotypic spectra and a variable expression of the disease. Molecular-genetic analysis of the causal PTEN gene may confirm or exclude the suspicion of the CS (3). We have analysed and described two patients (Publication 1 and 2) who presented with variable expression of the disease. First one manifested with massive polyposis of the gastrointestinal tract (GIT) and the other patient developed the malignant disease. Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterised by the presence of mucocutaneous...
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Molecular genetic analysis of the causes of selected hereditary forms of colorectal polyposis
Florianová, Martina ; Kohoutová, Milada (advisor) ; Křepelová, Anna (referee) ; Vodičková, Ludmila (referee)
Colorectal cancer (CRC) is one of the most common cancers worldwide. Hereditary colorectal adenomatous polyposis syndromes are a predisposition to colorectal carcinoma development. The most common analyzed syndromes are familial adenomatous polyposis (FAP) that results from germline mutations in the APC gene and MUTYH - associated polyposis (MAP) caused by germline mutations in the MUTYH gene. The aim of this study was to clarify genetics causes of colorectal polyposis in a set of probands without the germline mutation in the APC gene. Within studyʼs scope the presence of large deletion in APC gene was tested, there was looked for germline mutations in MUTYH gene, alternatively germline mutations in MSH6 gene by probands with monoallelic MUTYH mutation, item there was tested an effect of detected APC variants on gene expression. Screening for large deletions was performed by multiplex ligation dependent probe amplification (MLPA). A set of 120 APC-negative probands was examined for the presence of germline MUTYH mutations by denaturing high performance liquid chromatography (dHPLC). Subsequently a set of 145 APC-negative probands was screened only for germline MUTYH mutation in exon 7 and 13 by high resolution melting (HRM) analysis. Analysis of the effect on expression was tested by ten APC...
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Genetic Aspects of Sporadic Ovarian Cancer
Jančárková, Natalia ; Freitag, Pavel (advisor) ; Rokyta, Richard (referee) ; Kohoutová, Milada (referee)
58 9. SUMMARY Molecular biological parameters, including genetic alterations, present new and perspective direction in diagnostics, prediction of prognosis, monitoring and possible therapeutic approaches in oncological disease. The results presented have to do with the project, which is concentrated upon chromosomal rearrangements in ovarian and cervical cancer and their correlations with available parameters of both molecular biological and clinical characteristics. Sixty patients with ovarian cancer and twenty patients manifesting cervical cancer were included into the study. The histological type and grade, MIB-1 and p53 (using immunohistochemical method) were estimated by histopathologist. Both conventional karyotyping and molecular-cytogenetic methods (fluorescent in situ hybridization and comparative genomic hybridization) were applied to reveal chromosomal aberrations. The results were subjected to statistical evaluation, using analysis of variances and χ2 test. There were correlated parameters of quantitative and qualitative character - age, stage, histological type, grade, CA 125 before and after treatment, MIB-1, p53, surgical residuum, lymphadenectomy, response rate, chromosomal rearrangements. Analyses accomplished in ovarian cancer group revealed typical amplifications on chromosomes 1q, 3q and...
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