20.500.12556/RUL-173622 Analiza sprememb v nekodirajočih področjih genov, povezanih s podociti, pri bolnikih s Fabryjevo nefropatijo Analysis of variants in non-coding regions of podocyte-associated genes in patients with Fabry nephropathy Fabryjeva bolezen je redka genetska bolezen, ki nastane zaradi sprememb v genu GLA, kar vodi v zmanjšano ali odsotno aktivnost encima α-galaktozidaza A. Posledično pride v celicah do kopičenja glikosfingolipidov, kar prizadene več organskih sistemov. Ledvična prizadetost oziroma Fabryjeva nefropatija je pomemben zaplet bolezni, ki pomembno vpliva na kakovost življenja in preživetje bolnikov. Kljub napredku v zdravljenju in diagnostičnih metodah zgodnje odkrivanje in napovedovanje poteka Fabryjeve nefropatije še vedno ostaja izziv. Klasični biokemijski označevalci ledvične funkcije so nezadostni za odkrivanje zgodnjih okvar, poleg tega pa imajo lahko bolniki z enako genetsko spremembo zelo različen potek bolezni, na kar verjetno vplivajo še neznani genetski in okoljski dejavniki. Namen magistrske naloge je raziskati vlogo genetskih polimorfizmov v nekodirajočih regijah genov, pri razvoju in napredovanju Fabryjeve nefropatije. V raziskavo smo vključili 284 bolnikov s Fabryjevo boleznijo in jih razdelili glede na hitrost upada ocenjene hitrosti glomerulne filtracije, na skupino s stabilno ledvično funkcijo in skupino z napredujočo nefropatijo. Analizirali smo prisotnost desetih izbranih polimorfizmov v nekodirajočih regijah genov, ki so povezani z delovanjem podocitov, ki imajo ključno vlogo pri ohranjanju funkcije in integritete glomerulne pregrade. Za genotipizacijo smo uporabili kvantitativni PCR s hidrolizirajočimi sondami TaqMan. Rezultati so pokazali, da prisotnost določenih genotipov statistično značilno poveča tveganje za hitro napredovanje Fabryjeve nefropatije. Najpomembnejša polimorfizma sta bila identificirana v genu SHROOM3, kjer sta bila genotipa povezana z večjim tveganjem za hitrejše napredovanje Fabryjeve nefropatije. Naše ugotovitve potrjujejo, da genetski polimorfizmi v nekodirajočih regijah genov, povezanih z delovanjem podocitov, lahko pomembno prispevajo k razumevanju fenotipske variabilnosti Fabryjeve bolezni. S tem bi lahko v prihodnje omogočili bolj personaliziran pristop k spremljanju in zdravljenju bolnikov ter zgodnejše prepoznavanje bolnikov z večjim tveganjem za napredovanje bolezni. Fabry disease is a rare genetic disorder caused by mutations in the GLA gene, leading to reduced or absent activity of the enzyme α-galactosidase A. As a result, glycosphingolipids accumulate in cells, affecting multiple organ systems. Renal involvement, or Fabry nephropathy, is a major complication of the disease, significantly impacting patients’ quality of life and survival. Despite advances in treatment and diagnostic methods, early detection and prediction of the progression of Fabry nephropathy remain a challenge. Classical biochemical markers of kidney function are insufficient for identifying early damage, and patients with the same genetic mutation can experience highly variable disease progression, likely influenced by yet unknown genetic and environmental factors. The aim of this master’s thesis is to investigate the role of genetic polymorphisms in non coding regions of genes in the development and progression of Fabry nephropathy. We included 284 patients with Fabry disease, categorizing them according to the rate of decline in estimated glomerular filtration rate (eGFR) into a group with stable kidney function and a group with progressive nephropathy. We analyzed the presence of ten selected polymorphisms in non-coding regions of genes involved in podocyte function, as podocytes play a crucial role in maintaining glomerular barrier structure and function. Genotyping was performed using quantitative PCR with TaqMan hydrolysis probes. The results showed that the presence of certain genotypes significantly increased the risk of rapid progression of Fabry nephropathy. The two most significant polymorphisms were identified in the SHROOM3 gene, where the associated genotypes were linked to a higher risk of accelerated nephropathy progression. Our findings confirm that genetic polymorphisms in non-coding regions of podocyte-related genes can contribute substantially to understanding the phenotypic variability of Fabry disease. This knowledge could pave the way for a more personalized approach to patient monitoring and treatment and enable earlier identification of individuals at higher risk for disease progression. Fabryjeva bolezen Fabryjeva nefropatija podociti nekodirajoče regije genov enonukleotidni polimorfizmi kvantitativni PCR genotipizacija s sondami TaqMan Fabry disease Fabry nephropathy podocytes non-coding gene regions single nucleotide polymorphisms quantitative PCR TaqMan probe genotyping true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2025-09-19 08:45:23 2025-09-19 08:45:32 2025-11-11 03:49:38 0000-00-00 00:00:00 2025 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 118506 29001.pdf 29001.pdf 1 3D63D2DEFCDA685E37A29625861DC289 982b9fc66618a0f2868e2a6ef5413119d2d2dc487bef7a5ec0e69ac8daf8ea72 116c9f3a-9524-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=218228 Fakulteta za farmacijo 0 0 0