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Molecular-cytogenetic characterization of chromosomal breakages in peripheral blood lymphocytes of Fanconi anemia patients in different stages of the disease

dc.contributor.advisorJoksić, Gordana
dc.contributor.otherZeljić, Katarina
dc.contributor.otherStamenković-Radak, Marina
dc.contributor.otherJoksić, Gordana
dc.contributor.otherZeljić, Katarina
dc.creatorFilipović-Tričković, Jelena
dc.date.accessioned2019-05-16T10:19:18Z
dc.date.available2019-05-16T10:19:18Z
dc.date.available2020-07-03T08:14:31Z
dc.date.issued2018-12-14
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=6727
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/11019
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:19564/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025215666
dc.description.abstractČesta fragilna mesta (CFS) su hromozomski regioni skloni lezijama, suženjima i prekidima u uslovima replikativnog stresa in vitro. Najčešće se mogu naći kod sindroma hromozomskih nestabilnosti kao što je Fankonijeva anemija (FA), retka nasledna bolest koju karakteriše sklonost ka razvoju maligniteta i progresivna insuficijencija koštane srži, povećan broj hromozomskih prekida i radijala i telomerna fragilnost. Cilj ovog istraživanja je molekularno-citogenetička karakterizacija hromozomskih prekida u limfocitima periferne krvi, ispitivanje zajedničkog mesta javljanja - kolokalizacije prekida sa CFS i analiza mutacija u FANCD2 genu kod FA-D2 pacijenata iz Srbije kako bi se utvrdilo da li CFS zavise od tipa mutacija u FANCD2 genu. Navedeni parametri su analizirani kod pacijenata u različitim fazama bolesti kako bi se identifikovali prognostički parametri bolesti. Rezultati su pokazali da FA-D2 hromozomski prekidi kolokalizuju sa CFS, karakteristični su za komplementacionu grupu i distribucija im se menja sa progresijom bolesti. Učestalost radijala i telomernih fuzija značajno je viša kod pacijenata sa teškom insuficijencijom koštane srži i može predstavljati prognostički parametar bolesti. Radijali se formiraju između nehomologih hromozoma, uključujući i polne i autozome. Otkriveno je novo fragilno mesto u regionu 1q42.2. Sangerovim sekvenciranjem je otkriveno 10 varijanti FANCD2 gena, uglavnom dubokih intronskih, od kojih su tri novootkrivene (c.2396 C>A, c.206-246delG i c.2715+573 C>T). In-silico analizom identifikovane su tri patogene varijante kod više pacijenata koji nisu u srodstvu, koje mogu biti specifične za populaciju u Srbiji. Poređenje rezultata molekularno-citogenetičke i analize mutacija pokazalo je da ne postoji povezanost CFS i varijanti FANCD2 gena.sr
dc.description.abstractCommon fragile sites (CFSs) are chromosomal regions prone to gaps, constrictions and breaks under conditions of replication stress in vitro. They are mostly found in chromosomal instability syndromes such as Fanconi anemia (FA). FA is rare inherited disease characterized by cancer predisposition, progressive bone marrow failure, increased level of chromosomal breakages, radial figures and marked telomere fragility. The aim of this study was to perform molecular-cytogenetic characterization of chromosomal breakages and co-localization with CFSs in peripheral blood lymphocytes, as well as to analyze FANCD2 gene mutations in FA-D2 patients from Serbia. These parameters were monitored in patients at different stages of the disease in order to identify the prognostic parameters of the disease. The results of this study showed that FA-D2 chromosomal breakages co-localize with CFS, they are specific for the complementation group and their distribution pattern changes with the disease progression. The frequency of radials and telomere fusions is significantly higher in patients with severe bone marrow failure and could be of predictive value. Radials are composed of non-homologous chromosomes, including sex chromosomes as well as autosomes. One novel fragile site is found in region 1q42.2. Ten variants of FANCD2 gene are detected by Sanger sequencing, mostly in deep intronic regions, among which three are novel (c.2396 C>A, c.206-246delG i c.2715+573 C>T). In-silico analysis revealed three pathogenic variants in several unrelated patients, indicating their possible association to Serbian population. Matching the results of molecular-cytogenetic characterization and mutation analysis showed that there is no relationship between CFS and FANCD2 variants.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173046/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectČesta fragilna mestasr
dc.subjectCFSen
dc.subjectFanconi anemiaen
dc.subjecttelomere fusionsen
dc.subjectradialsen
dc.subjectFANCD2 variantsen
dc.subjectdeep intonic variantsen
dc.subjectbone marrow failureen
dc.subjectFankonijeva anemijasr
dc.subjecttelomerne fuzijesr
dc.subjectradijalisr
dc.subjectFANCD2 varijantesr
dc.subjectduboke intronske varijantesr
dc.subjectinsuficijencija koštane sržisr
dc.titleMolekularno-citogenetička karakterizacija hromozomskih prekida u limfocitima periferne krvi pacijenata obolelih od Fankonijeve anemije u različitim fazama bolestisr
dc.title.alternativeMolecular-cytogenetic characterization of chromosomal breakages in peripheral blood lymphocytes of Fanconi anemia patients in different stages of the diseaseen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/3358/Disertacija.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/3359/IzvestajKomisije20002.pdf


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