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Deletion Breakpoints of the CATCH22 Syndrome

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Deletion Breakpoints of the CATCH22 Syndrome University of Alberta Cat eye chromosome duplication breakpoints associated with the human cat eye syndrome cluster in two regions that correspond to deletion breakpoints of the CATCH22 syndrome Kerry Ellen MTaggatt 0 A thesis submitted to the Faculty of Graduate Studies and Research in partid fdfilhnent of the requirements for the degree of Master of Science Molecular Biology and Genetics Department of Biological Sciences Edmonton, Alberta Fd, 1997 National Library Bibliothèque nationale of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395. rue Wellington Ottawa ON K1A ON4 Oitawa ON K1A ON4 Canada Canada Ywr iUe Votre nifëfence Our rYe None nltéfenca The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seIl reproduire, prêter, distribuer ou copies of this thesis in microfom, vendre des copies de cette thèse sous paper or electronic formats. la fome de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts f?om it Ni la these ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Abstract CES is a rare, phenotypically variable human disorder resulting from a duplication of 22pter-22q11.2, typically in the form of a L supernumerary dicentric bisatellited cat eye chromosome, or CEC. CEG are divided into two groups based on the location of the two breakpoints. Through fluorescence in situ hybridization and quantitative dosage analysis, 1 have more specifically defined the locations of these breakpoints. 1 have demonstrated that the breakpoints of the smaller type I symmetrical CECç occur in a 450-650kb intemal corresponding to the published proximal deletion breakpoints assoàated with a second syndrome, CATCH22 The larger type II CEC duplications localize to the same interval as the CATCH22 syndrome distal deletion breakpoints. The clustering of rearrangement breakpoints in 22q11.2 may be the result of the presence of repetitive sequences, as has been demonstrated in conditions involving rearrangements of other chromosomes. First and foremost, 1 would like to thank my supervisor, Heather McDermid for her patience, wisdom, and assistance above and beyond the cdof duty over the last three years. Alberta Heritage Foundation for Medicd Research for hancial support Karen Romanyk, Dana Shkolny, and Angela Johnson for superb technical assistance and for seming on the "sanity maintenance" cornmittee The ~nninggang and the "Roaches" The McDermid lab for companionship and assistance in the lab John Locke, Mark Hicks, Andrew Simmonds, and jeff Hoyem for patiently assisting a cornputer illiterate The Puygroup in particular, Marcia Budarf for supplying "key" clones for the CEC breakpoint analysis and Barry Bamoski for over-the- phone and over-the-fax FISH technical advice John Groffen at the Children's Hospital Los Angeles for supplying plasmid CFXL Table of Contents Page Introduction Chromosome 22 ...................... ,.. .................................................... 1 Acquired malignant conditions..................................................... 4 Burkitt's lymphoma............................................................. 5 Chronic myelogenous leukemia ................. ............. -5 Ewing's sarcoma.................................................................... 5 22q duplication conditions.............................................................. 6 Cat eye syndrome Features................ ... ................................................... -6 History and etiology................................................. 11 CEC stability................................................................ 13 CEC duplication breakpoints .................................. 14 Other duplications associated with CES Interstitial duplications............................... 17 Unbalanced translocations............ ,.. .... -17 Normal chromosomes..................... .... ....... 18 Supernumerary ring chromosome ........... 18 Definition of the CES critical region Distal boundary ........................................... ..19 Proximal boundary ....................................... 20 Der(22)t(ll;22)(qU;ql1) syndrome..................................... 21 Tnsomy 22 .............................................................................. 21 Phenotypic comparison of trisomy 22, der(22)t(l 1;22)(q23;qll) syndrome, and CES.................. 27 22q deletion syndromes................................................................... 30 Clinical features DiGeorge syndrome .................................................. 30 Velocardiofacial /Shprintzen syndrome.............. 32 Conohuical anomaly face/Takao syndrome ..... 33 EtioIogy DiGeorge and Velocardiofacial syndromes ......... 35 Conotnuical anomaly face syndrome.................. 37 Isolated conotruncal heart defects......................... 40 Materials and Methods Human ceU/ tissue culture ............ ...........*...........*................***.....* -43 Freezing cells......................................................................... -43 Thawing cells......................................................................... 4 EBV transformation ............................................................. 4 Establishing a fibroblast culture ......................................... 46 Individuals used for analysis ............. .... .................................... 48 Human genomic DNA preparation From blood ............................................................................. 50 From cell culture................................................................... 50 Cosmid DNA preparation Srna11 scale alkaline lysis ..................................................... 51 Large scale QIAGEN ............................................................. 52 YAC DNA preparation .................................................................... 52 Restriction enzyme digestion ........................................................ -53 Southern transfer .............................................................................. 53 Southern hybridization ................................................................... 54 Quantitative dosage analysis.......................................................... 57 Fluorescence in sif u hybridization ............................................... 57 Cell preparation Lymphoblastoid cell lines...................................... -57 Fibroblast cultures ..................................................... 59 Slide preparation ................................................................... 59 Probe preparation Biotinylation ......................................................... -60 Probe p reannealing ................................................... 61 Hybridization....................................................................... 62 Post-hybridization Washes........................................................................ 63 Detection and amplification.................................. -63 Counterstaining and photograp hy ............ ... ...... 64 Reamplification........................................................ -64 Probes used for quantitative dosage and RFLP analysis ........... 65 Probes used for FISH analysis ......................................................... 66 Results Physical mapping YAC contig of the CESCR .................................................... 68 Map location of locus D22S111 (KI-197) ........................... 73 Breakpoints of cat eye chromosomes Patient phenotype ................................................................ -77 Localization of type 1 breakpoints ...................................... 77 PFGE localization of D22S427 ................................. 81 FISH analysis............................................................. -83 Quantitative dosage analysis ................................. -85 Localization of type IIa and type IIb CEC breakpoints ...94 FISH analysis .............................................................. 95 Supemumerary ring diromosorne .............................................. -101 Discussion Physical mapping.............................................................................. 107 Ca t eye chromosomes ..................................................................... -109 Breakpoints of type I CECs .................................................. 110 Pa tient CM11- CEC and interstitial duplication ............. 110 Breakpoints of type II CECs ................................................. 113 CEC breakpoint sumrnary: Involvement . of repetihve sequences...................................................... 115 Repetitive sequences involved in other conditions CMTlA/HNiPP .......................................................... 119 Hemophilia A ...........................................................-120 Inverted duplication chromosome 15/inv dup(15)s.... 122 Formation of inverted duplication chromosomes Paracentric inversion mode1................................. -129 U-strand exchange mode1......................................
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