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Molecular genetic analysis of chromosomal region 8q24 in patients with trichorhinophalangeal syndrome or isolated exostosis
Klugerová, Michaela ; Šolc, Roman (advisor) ; Křepelová, Anna (referee)
Trichorhinophalangeal syndrome is a malformation syndrome characterized by craniofacial and skeletal abnormalities and is inherited in an autosomal dominant manner. We distinguish free subtypes on clinical and molecular level - TRPS I, TRPS II, TRPS III. All TRPS patients have sparse hair, a pear-shaped nose, a long flat philtrum, a thin upper lip and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations and short stature are present. The subgroups TRPS I and TRPS III are result of the mutated TRPS1 gene, which is maped into the 8q24 region. This gene is situated proximal of the EXT1 gene, both genes are affected in a subgroup of patients with TRPS II. These patients suffer more from multiple (cartilaginous) exostoses and mental retardation. In this work we performed molecular genetic analysis of a sample of 16 patients, 8 probands showed a TRPS phenotype and 8 probands had only isolated exostoses. The peripheral venous blood of patients was used to gain purified DNA, which was subsequently used to investigate the chromosome 8q24 region using MLPA ("multiplex ligation-dependent probe amplification"). This analysis revealed a deletion in 1 TRPS patient and 1 patient with exostoses. Sequencing of the TRPS1 gene coding exons in remaining 7 TRPS...
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Genetics of Craniosynostosis.
Valterová, Simona ; Křepelová, Anna (advisor) ; Baxová, Alice (referee)
Craniosynostoses are premature fusions of one or more cranial sutures. They affect all cranial sutures and are the main symptom of many genetic syndromes. Syndromes connected with craniosynostosis are serious disorders associated with skeleton abnormalities, limb malformations or mental disability. These syndroms are caused by different mutations in FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, RECQL4, and RAB23 genes. The aim of this review was to summarize contemporary knowledge of phenotype and genetic basis of these diseases.
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Neurofibromatosis type 1 and NF1 germline mutations in Czech patients
Bendová, Šárka ; Křepelová, Anna (advisor) ; Kleibl, Zdeněk (referee) ; Kadlecová, Jitka (referee)
Neurofibromatosis type 1 (NF1, MIM 162200) is an autosomal dominant disorder affecting about 1 of 3000 live births, involving many cell types and organs, and associated with an increased risk of malignancy, predominantly of the central and peripheral nervous system 1. Tumour development is caused by inactivation of the NF1 tumour suppressor gene and subsequent cell cycle deregulation 2. Mutational analysis of NF1 is a challenge due to the presence of pseudogenes, large size of the gene, lack of mutational hotspots, and occurrence of a very diverse spectrum of mutations. There is no clear-cut genotype-phenotype correlation allowing accurate prediction of severity of the disorder. Only two mutations have been associated with a particular NF1 phenotype 3,4. This PhD thesis is composed of six publications dealing with NF1. Publications 1 and 6 are focused on NF1 mutation analysis in 67 patients from the Czech Republic. Genotypes and spectra of causal mutations are presented together with phenotypes of the patients and comparison of efficiency of various methods. Sporadic or familial cases with known germline mutation were distinguished by mutational analysis of other family members. This led to a hypothesis that the incidence of sporadic cases could had been overestimated in the past because of overlooked...
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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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Dwarfism. Pathogenesis with a special focus on genetic factors.
Procházková, Lucie ; Daňková, Pavlína (advisor) ; Křepelová, Anna (referee)
Nanism is a kind of disorder characterized by an extremely small figure. It can be caused by hormonal, genetic or metabolic defects. This work, which is composed by study of materials in the form of article and publication mainly by foreign authors, is concerned with chosen types of nanism and their pathogenesis. All these types of this disease are caused by genetic defects in following genes: FGFR3, COMP, COL2A1, DTDST and PTH/PTHrP. Point mutations arising de novo are frequent cause of nanism and mostly are inherited autosomal- dominantly. It's a large group of disorders with different seriousness level: from light form like multiple epiphyseal dysplasia to lethal form such as thanatophoric dysplasia.
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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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Microsatellite instability in hereditary nonpolyposis colorectal cancer patients
Sekowská, Martina ; Křepelová, Anna (advisor) ; Mareš, Jaroslav (referee) ; Kleibl, Zdeněk (referee)
Detection of microsatellite instability (MSI) is the standard part of mutational analysis in hereditary nonpolyposis colorectal cancers (HNPCC). Characteristic phenotypic feature of MSI indicates loss of mismatch repair (MMR) in tumor cells. We studied MSI in 205 tumors from 152 patients with HNPCC. Of these, 37 patients fulfilled Amsterdam criteria, 72 patients were familial and 43 were sporadic cases. We used methods of fragmentation analysis on polyacrylamide gel and/or with fluorescent labelled primers (ABI Prism 310 Genetic Analyzer). Three mononucleotide (BAT-RII, BAT-25, BAT-26) and five dinucleotide (D2S123, D3S1029, D5S346, D17S250, D18S58) repeat loci were analysed. We detected 75 tumors with high degree of MSI (MSI-H), 12 tumors with low degree of MSI (MSI-L) and 118 tumors with stable microsatellites (MSS). In 44 of these, loss of heterozygozity (LOH) was found. In 30 patients with MSI-H tumors a mutation in one of mismatch repair genes was detected. Microsatellite analysis was positively correlated with immunohistochemical detection of MLH1 and MSH2 proteins.
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