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Aberrant Glycosylation in HEMPAS Patients Aberrant Glycosylation in HEMPAS Patients Homa Kameh A thesis submitted in conformity with the requirements for the degree of Master of Science Ins titute of Medical Sciences University of Toronto O Copyright by Homa Kameh 1997 National Library Bibliothèque nationale of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395, nie Wellington Ottawa ON K1A ON4 OttawaON KtAON4 Canada Canada Your lJe Votre retermw Our iUe Noire fefêfenfe The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant a la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distribuer ou copies of this thesis in microfom, vendre des copies de cette thèse sous paper or e1ectron.c formats. la forme de microfiche/nlm, 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 fkom it Ni la thèse ni des extraits substantiels may be printed or othedse de celle-ci ne doivent être imprimes reproduced without the author7s ou autrement reproduits sans son permission. autorisation. Aberrant Glycosylation in HEMPAS Patients Homa Kameh Master of Science, 1997 lnstitute of Medicai Sciences, University of Toronto ABSTRACT HEMPAS (hereditay erythroblastic mdtinuclearity with positive acidified serurn lysis test) is a rare congcnital anernia. A group of enzymatic lesions affecting the biosynthesis of N-linked oligosaccharides has been reported in HEMPAS. This study was conducted to investigate the molecular basis of KEMPAS in a group of Ontario patients. Lectin binding and endoglycosidase digestions were utilized to determine the nature of abnormal oligosaccharides on two erythrocyte membrane giycoproteins, Bands 3 and 4.5. The results suggest a hybrid or high mannose N-glycan in place of poly N- acetyUactosamine on these proteins, consistent with a defect in a-mannosidase II. A reduction in the enzymatic activities of GnT II or P4GdT. as reported in some HEMPAS patients, was not detected in the cdtured EBV-tnnsformed lymphobiasts of Our patients. Moreover, poly N-acetyllactosamine was present on proteins in these cells. The alteration in the oligosaccharide moiety of Band 4.5 did not interfere with its glucose transport ACKNO WLEDGMENTS My greatest appreciation goes to my supervisor, Dr. Reinhart Reithrneier, for believing in me. Without his guidance and support this thesis would not have been possible. His knowledge and admirable personality offered me the best example to follow dunng my graduate program. I thank Dr. Harry Schachter for his CO-supervision,his patient sharing of his expertise in glycobiology and for ail those sessions of "clariQing things". I also thank my supervisory cornmittee member, Dr. Robert Murray for his constructive comrnents which helped me to improve rny work. I thank my parents for their support and patience even though they could not elaborate on what their girl was doing. Bahnm and Pari be thanked for their understanding and their constant presence beside me. My thanks to Mark Gettner, Dr. Vieth and Dr. Jahromi for their inspiring words and for wnting those recommendation Ietters. I thank Dr. Whiteside for her willingness to offer expert comrnents in the annual meetings. Dr. Carolina Landolt-Marticorena and Lisa Tam are thanked for their generosity with their knowledge and for helping me get started. 1 thank Dr. Ieffrey Chanik, Dr. Tip Loo, Dr. Ienny Tan, Dr. Gary Song, Bryan Loo, Denise Eskinazi and Anita Nutikka for their technical assistance. 1 also thank my labrnates Milka, John, and Jing for sharing the rare and joyful moments of "some good results"! Last but not least 1would like to thank rny friends: Susan, Valerie, Martine, Simin, Emily, Mark, Michael and Has for their heart warming words and being always there for me. They ail share this degree with me. 1 especiaily thank Edyfor moral support and her "emo tional intelligence". TABLE OF CONTENTS I . INTRODUCTION ....................... ..... ....................................*...................*.....................1 I .I PROTEIN-LINKED OLIGOSACCHARIDES ........................................................................L i. 1.1 Biosynthesis of N-giycans .........................................................................................-3 1.1.1.1 Synthesis of dolichoi-iinked sugar precursor ......................................................2 1.1.1.2 Oiigosaccharyi transferase ................................................................................ 6 1.1.1.3 Trimming of the N-linked high mannose precursor .............................................6 1.1.1.4 Glycosyitransferase characteristics................................................................... 1 O 1.1.1.4.1 Domain structure of giycosyltransferases ..................................................1 O 1.1.1.4.2 Retention and targeting of the glycosyiation enzymes ............................... 1 2 1.1.2 Poly N-acetyiiactosamine ....................................................................................... 1 3 1.1.2.1 Poiy N-aceryi factosamine synthesis ...............................................................1 3 1.1.2.2 Distribution of poiy N-acetyliactosamine ..................................................1 6 1.1 .2.3 Poiy N-acetyllactosamine as blood group antigens.......................................... 1 9 1.1.3 Characterizarion of oligosaccharides...................................................................... 20 1.1.3.1 Lectins ............................................................................................................. 1.1 .3.2 Endoglycosidases ........................................................................................... .-37 - 1.2 THE ROLE OF CARBOHYDRATES ON MEMBRANE GLYCOPROTEINS ...........................24 1.7.1 Eariy foiding and protein stubiiiry .........................................................................24 1.2.2 Chaperon-facil itated foiding .................................................................................-25 1.2.3 Sorting and rargeting of glycoproteins .................................................................. -26 1.2.4 Clearance of serum glycoproteins ...........................................................................2 7 1.2.5 Celi-cell interactions............................................................................................... 2 8 1.2.6 Funclional roie of oiigosaccharides....................................................................... 2 9 ERYTHROCYTEMEMBRANE GLYCOPROTEINS ............................................................40 I.3 .......................................................................................................... 3.1 Giycoplio. rin 4. - L 1.3.2 Band 3 ................................................................................................................... 42 1.3.3 Glucose transporter............................................................................................... -44 1.4 ER YTHROPOIESIS ........................................................................................................ 45 1.5. HEMPAS ..................................................................................................................... 50 1.5.1 Ciinicai features ..................................................................................................... 52 1.5.2 Hemato logical jèatur es. .......................................................................................... 5- 2A 1.5.3 Sero fogicai features ................................................................................................3 3 1.5.4 Biochemistry........................................................................................................... 5 4 1.5.5 Treatment............................................................................................................... 5 5 1.5.6 Moiecular abnormalities in HEMPAS .....................................................................5 5 1.5.7 Abnomalities in glycosyiation enqmes in HEMPAS.............................................. -5 8 1.5.8 HEMPAS and other "diseases of aberrant giycosyiation "....................................... 6 1 1.6 RESEARCH PROJECT AND HYPOTHESIS ...................................................................... 6 3 II . MATERIALS AND METHODS ....................................... ...................................m.....*64 11.1 MATERIALS................................................................................................................ 64 11.2 METHODS .................................................................................................................... 67 11.2.1 Preparation of ghost membranes........................................................................... 67 11.2.7 Prepomtion of cell extracts ................................................................................... 67 11.2.3 Enqmatic digestion of oiigosaccharides............................................................... 67 11.2.4 Lech Biots ........................................................................................................... 68 11.2.5 Western Biots .......................................................................................................
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