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Molecular-genetic basis of congenital adrenal hyperplasia in Serbia: characterization of mutations in CYP21A2 gene

dc.contributor.advisorUgrin, Milena
dc.contributor.otherPavlović, Sonja
dc.contributor.otherJelić, Mihailo
dc.creatorMilačić, Iva D.
dc.date.accessioned2017-12-14T14:41:32Z
dc.date.available2017-12-14T14:41:32Z
dc.date.issued2017-09-29
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=5439
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:16824/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025171634
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/8960
dc.description.abstractKongenitalna adrenalna hiperplazija (KAH) obuhvata grupu autozomno recesivnih oboljenja okarakterisanih narušenom sintezom steroidnih hormona u kori nadbubreţne ţlezde i širokim spektrom kliniĉkih simptoma. Na osnovu fenotipske ekspresije razlikuju se klasiĉna (jednostavna virilizujuća i forma sa gubitkom soli) i neklasiĉna forma bolesti. U više od 90% sluĉajeva javlja se zbog deficijencije enzima steroid 21-hidroksilaze (CYP21A2) kао posledicе prisustva mutacija u CYP21A2 genu. Dva osnovna mehanizma dovode do inaktivacije CYP21A2 gena: nejednaka razmena delova homologih sekvenci izmeĊu nesestrinskih hromatida u mejozi moţe dovesti do formiranja CYP21A1P/CYP21A2 himernih gena ili delecije celog CYP21A2 gena, dok se putem genske konverzije u aktivan gen kopiraju homologe, ali defektne sekvence CYP21A1P pseudogena. Zbog varijabilnosti i kompleksne strukture regiona u kome je lociran CYP21A2 gen molekularna dijagnostika KAH-a i danas predstavlja izazov. Ovo je prva studija molekularno-genetiĉke osnove KAH-a u Srbiji. Izvršena je optimizacija PCR-SSP i metode direktnog DNK sekvenciranja CYP21A2 gena ĉime je omogućena detekcija CYP21A1P/CYP21A2 himernih gena, mutacija nastalih genskom konverzijom, ali i retkih i novih genetiĉkih varijanti. UtvrĊen je celokupan spektar mutacija kao i njihove uĉestalosti kod 61 nesrodnog pacijenta. Identifikovano je 18 alela sa patogenim efektom i dostignut je nivo detekcije mutacija od 82,0%. Nivo detekcije je bio najviši (94,7%) u grupi pacijenata sa najteţom formom bolesti (klasiĉni KAH sa gubitkom soli). Najuĉestalija mutacija u populaciji iz Srbije, kao i u većini drugih populacija, je c.290-13A/C>G (18,5%). Pet uĉestalih alela koji ukljuĉuju c.290-13A/C>G, CYP21A1P/CYP21A2, p.P30L, p.R356W i p.G110fs mutacije ĉine 63,0% svih mutiranih CYP21A2 alela u analiziranoj grupi pacijenata. Primećena je neuobiĉajeno visoka uĉestalost p.R356W mutacije (11,1%), kao i kompleksnih alela sa višestrukim mutacijama (7,4%), meĊu kojima ĉak 75,0% sadrţi p.P453S mutaciju...sr
dc.description.abstractCongenital adrenal hyperplasia (CAH) comprises of group of autosomal recessive disorders characterized by impaired adrenal steroidogenesis and wide spectrum of clinical manifestations. There are two main phenotypes: classical (salt wasting and simple virilizing) and non-classical form. In more than 90% of patients the disease is caused by steroid 21-hydroxylase (CYP21A2) deficiency resulting from underlying CYP21A2 gene mutations. Two major molecular mechanisms lead to CYP21A2 gene inactivation: unequal crossing over results in CYP21A1P/CYP21A2 chimerae formation or whole CYP21A2 gene deletion, whereas gene conversion copy homologue, but defective sequences from CYP21A1P pseudogene to the active gene. Due to variability and complex structure of the region where CYP21A2 gene resides molecular diagnostics of congenital adrenal hyperplasia remains a challenge. This is a first comprehensive study regarding molecular genetic basis of CAH in Serbia. Optimization of PCR-SSP and direct DNA sequencing of CYP21A2 gene was conducted, thus enabling detection of CYP21A1P/CYP21A2 chimerae, pseudogene derived mutations, but also rare and new genetic variants. Analysing 61 unrelated patients complete mutational spectrum, as well as mutation’s frequencies, was determined. Eighteen pathogenic alleles were identified and detection rate of 82.0% was assessed. Detection rate was highest (94.7%) in patients with severe classical form with salt wasting. The most frequently occurring mutation in patients from Serbia, as well as in many other populations, is c.290-13A/C>G (18.5%). Five alleles including c.290-13A/C>G, CYP21A1P/CYP21A2, p.P30L, p.R356W and p.G110fs mutations account for 63.0% of all mutated CYP21A2 alleles in analysed patients. Unusually, high frequency of p.R356W mutation (11.1%), as well as complex alleles with multiple mutations (7.4%), most frequently including p.P453S (75.0%), was detected. Direct DNA sequencing unravelled two new missense mutations p.L129P and p.S165P, for which computer predictions showed to be probably pathogenic...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.rightsAutorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
dc.sourceУниверзитет у Београдуsr
dc.subjectdeficijencija steroid 21-hidroksilaze, CYP21A2 gen, detekcija mutacija, CYP21A1P/CYP21A2 himerni geni, genotip-fenotip korelacija, dijagnostiĉki algoritamsr
dc.subjectsteroid 21-hydroxylase deficiency, CYP21A2 gene, mutation detection, CYP21A1P/CYP21A2 chimerae, genotype-phenotype correlation, diagnostic algorithmen
dc.titleMolekularno-genetička osnova kongenitalne adrenalne hiperplazije u Srbiji: karakterizacija mutacija u CYP21A2 genusr
dc.title.alternativeMolecular-genetic basis of congenital adrenal hyperplasia in Serbia: characterization of mutations in CYP21A2 geneen
dc.typePhD thesis
dcterms.abstractУгрин, Милена; Павловић, Соња; Јелић, Михаило; Милачић, Ива Д.;


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