Analiza znanih genetskih različic bolezni mrežnice makularne telangiektazije tipa 2 (MacTel 2) pri slovenskih pacientih

Tkalec, Nuša (author), Debeljak, Nataša (mentor)

: Makularne telangiektazije tipa 2 (MacTel) spadajo med redke degenerativne bolezni mrežnice, za katere so značilne spremembe v morfologiji in mrežničnem mikrokolju. Začetki raziskovanja te bolezni so bili osredotočeni na raziskovanje MacTel kot vaskularne (žilne) bolezni, z napredkom diagnostičnih metod, ki omogočajo vedno boljši vpogled v strukturne in funkcionalne spremembe v očesu, pa se spreminja tudi opredelitev bolezni. Raziskovalci so ugotovili, da gre za primarno nevrodegenerativno bolezen, sekundarno pa se razvijejo žilne spremembe (telangiektazije, neovaskularizacija). Natančen vzrok bolezni ni znan, ker se pojavlja pri več družinskih članih in dvojčkih se predpostavlja, da ima genetsko ozadje. Namen raziskovalne naloge je bila analiza z boleznijo povezanih genetskih različic za opredelitev njihove pojavnosti pri izbrani kohorti slovenskih pacientov. V ta namen smo v prvem delu raziskovalnega dela s pregledom obstoječe literature in baz podatkov podrobneje analizirali molekularno-genetsko ozadje MacTel, s poudarkom na pregledu genov, njihovih povezav z drugimi proteini in presnovnih poteh. Ovrednotili smo pomen predhodno izbranih različic genov PHGDH, CPS1, CERS4, MIR9-2HG, SLC20A6, REEP3 ter SPTLC1 pri razvoju bolezenskega fenotipa. Rezultati teoretičnega pregleda so potrdili vpletenost izbranih različic v presnovnih poteh aminokislin in lipidov ter za pet od sedmih različic predvideno povezavo različice s funkcijo ali strukturo proteina. V drugem delu raziskovalnega dela smo z uporabo sond TaqMan eksperimentalno preverili prisotnost izbranih različic genov v kohorti slovenskih pacientov. Preverili smo prisotnost sedmih izbranih različic pri 67 pacientih z diagnozo MacTel in osmih družinskih članih ter pridobili vpogled v sopojavnost različic. Rezultate genotipizacije smo statistično ovrednotili in primerjali s predhodnimi dognanji. Ugotovili smo, da se izbrane različice, ki so bodisi zaščitne (redkejše pri pacientih) bodisi bolezenske (pogostejše pri pacientih), pojavljajo tudi pri slovenskih pacientih. Rezultati raziskovalnega dela so prispevali k boljšemu razumevanju razširjenosti in vloge izbranih genetskih različic pri slovenskih pacientih z diagnozo MacTel. Nadaljnje raziskave bodo omogočile razumevanje vloge presnovnih poti na razvoj bolezni ter razvoju ciljno usmerjene molekularno-genetske diagnostike za to kompleksno degenerativno bolezen mrežnice.

• Language: Slovenian
• Keywords: makularne telangiektazije tipa 2 (MacTel), presnovne poti, genetske različice, molekularno-genetska analiza
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Year: 2025
• PID: 20.500.12556/RUL-171786
• COBISS.SI-ID: 252649731
• Publication date in RUL: 02.09.2025

Secondary language

• Language: English
• Title: Identification of known genetic variants in retinal disease macular telangiectasis type 2 (MacTel2) in Slovenian patients

Abstract

Macular telangiectasia type 2 (MacTel) is a rare degenerative retinal disease characterized by changes in retinal morphology and its' microenvironment. Initial research described MacTel as a vascular disease. With improved imaging techniques that allow better visualization of retinal structure and function, this view has shifted. It is now understood that MacTel is primarily a neurodegenerative disorder, with vascular changes such as telangiectasia and neovascularization arising as secondary effects. The exact cause of the disease remains unknown, but since it occurs in multiple family members and twins, it is assumed to have a genetic background. The aim of this work was to analyze genetic variants already associated with the disease to determine their frequency and significance for the onset of MacTel in a selected cohort of Slovenian patients. In the first part of research, we conducted a detailed analysis of the molecular-genetic background of MacTel by reviewing existing literature and databases, focusing on the metabolic pathways involving these genes and their interactions. We evaluated the relevance of previously identified variants in the PHGDH, CPS1, CERS4, MIR9-2HG, SLC20A6, REEP3, and SPTLC1 genes in the context of MacTel pathogenesis. The theoretical overview confirmed the involvement of selected variants in amino acid and lipid metabolic pathways and a potential link between the variant and protein function or structure for five of the seven variants. In the second part of the study, we experimentally assessed the presence of selected gene variants in a cohort of Slovenian patients using TaqMan probes. We analyzed the presence of seven selected variants in 67 patients diagnosed with MacTel and eight family members and examined the co-occurrence of each selected variant. The genotyping results were statistically evaluated and compared with previous findings. We have determined that the selected variants, which are either protective (less frequent in patients) or pathogenic (more frequent in patients), also occur in Slovenian patients. The results of this research contributed to a better understanding of the prevalence of selected genetic variants in Slovenian patients diagnosed with MacTel and highlighted the crucial role of in-depth understanding of associated metabolic pathways in developing targeted molecular-genetic diagnostics for this complex degenerative retinal disease.

• Keywords: Macular Telangiectasia Type 2 (MacTel), Metabolic Patways, Genetic Variants, Molecular-Genetic Analysis