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Genetic and clinical aspects of the restless legs syndrome
Pavlíčková, Jana ; Kemlink, David (advisor) ; Seeman, Pavel (referee) ; Martásek, Pavel (referee)
Introduction: The Restless Legs Syndrome (RLS) is a frequent neurological disorder with a prevalence ranging from 5 - 10%. RLS is characterized by an urge to move the lower extremities during the night, thus RLS causes sleep disturbance. It presents as both idiopathic and secondary form. Idiopathic RLS is associated with common genetic variants in MEIS1, BTBD9, PTPRD and MAP2K5/SCOR1. Recently, multiple sclerosis (MS) was identified as a common cause for secondary RLS, the prevalence of RLS in patients with MS ranges from 13.3 to 37.5%. The aim of our study was to analyse the clinical and genetic aspects of this disorder, especially in patients with multiple sclerosis. In the clinical part, we evaluated the prevalence of RLS among Czech patients with MS and we compared the extent of brain damage between patients with and without RLS using magnetic resonance imaging (MRI). In the genetic part, we further analysed the impact of known genetic variants (MEIS1, BTBD9, MAP2K5/SCOR1, PTPRD) for RLS in other European populations and in patients with MS. Methods: Clinical part: Each patient with MS underwent a semi-structured interview. A patient was considered to be affected by RLS if he/she met all four standard criteria at life- long interval. Lesion load (LL - T2), brain atrophy - T1 and brain...
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Structural studies and tissue distribution of human GCPII and characterization of its rat and porcine orthologs
Rovenská, Miroslava ; Konvalinka, Jan (advisor) ; Jonák, Jiří (referee) ; Martásek, Pavel (referee)
Since GCPII is a potential pharmacological target, it is being extensively snrdied in many labs all around the world and these studies comprise many topics. This is minored also by this PhD thesis. The papers included here concem two major issues: 1. analysis ofGCPII structure and interactions with ligands; 2. study of CCPII distribution in tissues of human and two other species considered as potential animal models and kinetic characterization of the corresponding GCPII orthologs. Structural studies of GCPII active site and substrate binding are driven by the attempt to broaden the information that could help the rational design of novel small GCPII ligands, functioning either as inhibitors in neuronal damage or as imaging agents in cancer diagnosis. Two papers included in this thesis describe ligand binding in the GCPII active site in detail, with particular ernphasis on the Sl'pocket in one case and on the Sl pocket in the other' Based on our findings, we can describe a set of interactions goveming GCPII affinity to a substrate, accommodations that CCPII active site is capable of during ligand binding, the limits imposed on the ligand and tolerance of the enzyme to varying ligand nature. All these pieces of infomation are useful for the design of novel compounds with high affinity to GCPII' sufÍicient...
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Molecular pathology of selected inherited hyperbilirubinemias
Šlachtová, Lenka ; Martásek, Pavel (advisor) ; Schneider, Bohdan (referee) ; Králová, Jarmila (referee)
Inherited hyperbilirubinemias are a group of metabolic disorders, characterized by increased levels of total serum bilirubin or its conjugated fraction. Most of these hyperbilirubinemias are inherited autosomal recessively and are manifested in young age. Increased bilirubin reflects the genetic disturbances in one of the enzymes of heme degradation pathway, the defect of bilirubin conjugation (UGT1A1 gene) or its transport (ABCC2, OATP1B1, OATP1B3). All of these proteins are involved not only in elimination of bilirubin, but various substrates; therefore the performed studies have a great pharmacogenomics impact. We have studied the molecular pathology of hereditary hyperbilirubinemias in Caucasian and Roma population and to compare the clinical and biochemical results with the molecular genetic data. We described the impact of compound defect of c.-3279T>G and g.175492_175493insTA on total serum bilirubin and calculated the linkage disequlibrium of these two variants in promoter region of UGT1A1 gene. We also verified, that the population distribution of both variants is in concordance with the literature. In our second study, we have described the rare conjugated hyperbilirubinemia Dubin-Johnson type among 7 Roma families. We have found a novel variant NG_011798.1:c.[1013_1014delTG] together with...
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