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|9 (HR-ZaNSK)218938
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|a eng
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|a 616-002:575(497.7)
|2 MRF 2011.
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|a (497.7)
|2 MRF 2011.
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|a Petreska, Lidija
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|a Molecular characterization of cystic fibrosis in Macedonia :
|b doctoral Thesis /
|c Lidija Petreska.
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|a Zagreb :
|b L. Petreska,
|c 1996
|e ([s. l. :
|f s. n.])
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|a 173 lista :
|b ilustr., table, graf. prikazi ;
|c 30 cm.
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|a Mentor: Georgi D. Efremov
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|a Sveučilište u Zagrebu, Prirodoslovno-matematički fakultet, Zagreb, 1996
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|a Bibliografija: str. 140-162
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|a Sažetak
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|a Abstract: Cystic fibrosis (CF) is a common cause of childhood death, inherited in an autosomal recesive mode. Its incidence is estimated to be approximately 1 in 2500 among the Caucasian population [1]. The major clinical symptoms are result of structural changes and gradual loss of function of the secretory epithelial cells (specially the pancreatic cells), and a susceptibility of the lower respiratory airways to severe and chronic infections, because of an abnormality in the transmembrane transport for chloride ions. The gene responsible for CF was identified and characterized in 1989 by the techniques of "reverse genetic" and was called cystic fibrosis transmembrane regulator (CFTR) gene [9-11].
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|a Expression of the disease varies from very mild to highly expressed severe clinical forms, due to the heterogeneity of the defects at the molecular level [12]. The aim of this dorctoral thesis was to determine the molecular basis of CF in patients from the Republic of Macedonia. The DNA methodology used included characterization of CFTR mutations in the exons (and flanking sequences) of the gene, and characterization of extragene and intragene polymorphisms, through: PCR amplification, and subsequent analyses of PCR products by agarose or polyacrylamide gel electrophoresis, dot blot hybridization, restrict digestion, single strand comformation polymorphism, constant denaturing gel electrophoresis, denaturing gradient gel electrophoresis, and squencing.
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|a Statistical analyses was used to corellate the rsults from DNA analyses to the clinical expression of the disease. Eighty three unrelated CF patients and their families were studied. The molecular characterization resulted in determination of 58.4% (97/166) of the CF chromosomes. Nine different CFTR gene mutations were found, with the following frequencies: F508 (47.6%), G542X (3.6%), N1303K (1.8%), 621+1G-]T (1.2%), 711+3A-]G (1.2%), 3849-]A 1.2%), 457TAT-]G(o.6%), 1811+1G-] (0.6%), V139E (0.6%). Mutations 711+3A-]G, 1811+1G-]C, and V1397E were newly discoveres mutations [158,282]. Another mutation, (Y569C), was also described for the first time, in a CF family from Croatia [283]. Eight known polymorphisms (R75Q, 405+46G/T, 875+40A/G, L467P, M470V, T966T, 3041-92G/A and 4002A/G),
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|a and one new polymorphism (P324P) in the CFTR gene were characterized in 28 (23 and 5 undertermined) chromosomes [284]. The haplotype analysis of the CF linked XV-2c and KM19 polymorphic loci of 118 CF and 115 normal chromosomes, have shown significantly different frequency distribution among the CF compared to the normal chromosomes. Haplotype B is the major haplotype among the F508 chromosomes (76.4%), whilw haplotype C is the most frequent among the non F508 chromosomes (36.5%%). The analysis of the correlation between the genotype and the clinical data of 76 patients, showed association of the molecular defects with the phenitype expressed at the level of exocrine pancreatic function, while the sweat chloride levels and the overall severity of the disease showed marked variations.
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|a The results of this study will be of great help in clinical prognosis of the CF disease in the patients. Sixteen prenatal diagnoses were performed as a practical achivement of the results of this doctoral thesis.
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|a Abstrakt:Cistična fibroza (CF) je jedan od njačešćih nasljednih uzroka smrti kod djece. Nasljeđuje se autosomno recesivno. Incidence je oko 1 u 2500 ljudi u bijeloj populaciji [1]. Zbog abnormalnosti u transmembranskom transportu za kloridne ione kod sekretornih epitelnih stanica (osobito pankreastih) nastaje postepeni gubitak funkcije. Doljnji respiratorni putovi su podložni teškim i kroničnim infekcijama. Gen odgovoran za CF otkriven je i karakteriziran pomoću tehnika "reverzne genetike" i nazvan cistično fibrozni transmembranski regulator (CFTR) gen [9-11]. Heterogenost molekularnih defekata u genu uzrokuje u pacijentima ekspresiju bolesti od blagih do vrlo teških kliničkih formi [12]. Cilj ovog doktorskog rada je da utvrdi molekularnu osnovu cistične fibroze kod pacijenata iz Republike Makedonije.
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| 520 |
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|a Korišćene su sledeće metode DNK u karakterizaciji CFTR mutacija i intragenskih i ekstragenskih polimorfizama: amplifikacija DNK pomoću polimerazno-lančaste reakcije (PCR); analiza produkata PCR amplifikacije pomoću agarozne ili poliakrialamidne gel elektroforeze, digresije restrikcijskim endonukleazama, dot blot hibridizacije, jednostaničnim konformacijskim polimorfizmom, denaturiračkom gradijent gel elektroforezom i sekvenciranjem. Ispitivanja su vršena kod 83 pacijenata sa CF i članovima njihovih obitelji, podritlom iz Makedonije. Karakterizirano je 58.4% (97/166) CF kromosoma. Nađeno je devet različitih mutacija u CFTR genu, sa sledećom frekvencijom: F508(47.6%), G542X(3.6%), N1303K(1.8%), 621+1G-]T(1.2%), 711+3A-]G(1.2%), 3849G-](1.2%), 457TAT-](0.6%), 1811+1G-]C(0.6%), V1397E(0.6%).
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|a Mutacije 711+3A-]G, 1811+1G-]C, V1397E su novootkrivene i karakterizirane prvi put tokom ove studije [158,282]. Također je po prvi put opisana i nova mutacija (Y569C) u CF obitelji iz Hrvatske [283]. Kod 28 kromosoma (23 CF i 5 neodređenih) je otkriveno postojanje 9 različitih polimorfizama CFTR gena (R75Q, 405+46G/T, 875+40A/G, P324P, L467P, M470V, T966T, 3041-92G/A). Polimorfizam P324 je otkriven i karakteriziran po prvi put u litaraturi [284]. Analiza haplotipova za XV-2c i KM19 polimorfnih mjesta kod 118 CF i 115 normalnih kromosoma su potvrdila postojanje signifikantne razlike u distribuciji haplotipova između CF i normalnih kromosoma. Haplotip B je nađen kod 76.4% 508 kromosoma. Haplotip C je najčešćih kod non F508 kromosoma (36.5%). Poznavanje molekularne osnove CF našla je praktičnu primjenu u prenatalnoj dijagnozi ove nasljedne bolesti.
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|a U toku ovg rada izvršene su 16 prenatalnih dijagnoza za CF. Ispitivanja zavisnosti kliničke slike bolesti od prirodne mutacije u CFTR genu kod 76 pacijenata sa cističnom fibrozom su potvrdila asociranost sa egzokrinom funkcijom pankreasa. Srednja koncentracija klorida u znoju i težina bolesti jako variraju između genotipa i u okviru jednog genotipa.
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| 650 |
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7 |
|a Cistična fibroza
|z Sjeverna Makedonija
|x Genetički aspekti
|2 nskps
|
| 700 |
1 |
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|a Efremov, Georgi D.
|4 cns
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| 981 |
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|p CRO
|r HRB1996
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| 998 |
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|c mzoi110614
|c sdip150320
|
| 852 |
4 |
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|j DCD-ZG-69/98
|
| 876 |
|
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|e DCD
|a 69/1998
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| 886 |
0 |
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|2 unimarc
|b 07200nam0 2200373 450
|