UvA-DARE (Digital Academic Repository) Genetic basis of rare blood group variants Wigman, L. Publication date 2013 Document Version Final published version Link to publication Citation for published version (APA): Wigman, L. (2013). Genetic basis of rare blood group variants. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:06 Oct 2021 Genetic basis of rare blood group variants Financial support was granted by: Joop en Annelies Wigman, Philippine Sanquin Blood Supply, Amsterdam Amsterdam Medical Center, Amsterdam MRC-Holland b.v., Amsterdam ISBN: 978-90-5335-759-0 Cover: Wouter Wigman and Lonneke Haer-Wigman Lay-out: Simone Vinke, Ridderprint B.V., Ridderkerk, the Netherlands Printing: Ridderprint B.V., Ridderkerk, the Netherlands Genetic basis of rare blood group variants ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op dinsdag 3 december 2013, te 12:00 uur door Lonneke Wigman geboren te Terneuzen Promotor: Prof. dr. C.E. van der Schoot Copromotor: Dr. M. de Haas Overige leden: Prof. dr. F. Baas Prof. dr. E. Bakker Prof. dr. M.H.J. van Oers Prof. dr. W.H. Ouwehand Prof. dr. J.J. Zwaginga Faculteit der Geneeskunde Contents Chapter 1 General introduction and scope of this thesis 7 Chapter 2 Comprehensive genotyping for 18 blood group systems using a 27 multiplex ligation-dependent probe amplification assay shows a high degree of accuracy Chapter 3 RHD and RHCE variant and zygosity genotyping via multiplex 51 ligation-dependent probe amplification Chapter 4 Characterization of known and novel RHD variant alleles in 37.764 79 Dutch D- pregnant women Chapter 5 SMIM1 underlies the Vel blood group and influences red blood cell traits 103 Chapter 6 Genetic screening for the Vel- phenotype circumvents difficult 123 serological screening due to variable Vel expression levels Chapter 7 Molecular analysis of immunized Lan- or Jr(a-) patients and validation of 143 genotyping assays to screen blood donors for Lan- and Jr(a- )phenotype Chapter 8 Familial azotemia is caused by a duplication of the UT-B transporter 161 Chapter 9 General discussion 173 Appendix Nederlandse samenvatting 183 Dankwoord 191 Curriculum Vitae 195 Lijst met publicaties 197 Portfolio 199 Chapter 1 General introduction and scope of this thesis General introduction Red blood cells carry and deliver oxygen to all cells of our body and are therefore essential for human life. During trauma huge amounts of red blood cells can flow out of the body. A massive loss of red blood cells will lead to the failure of oxygen transport to vital organs, such as the heart and brain, resulting in death. Furthermore, Chapter 1 Chapter some individuals have a defect in erythropoiesis (for instance thalassaemia) which can cause constitutional anemia. To relieve massive blood loss after trauma or to relieve anemia in patients with an erythropoiesis disorder, red blood cells from a donor can be transfused. Donor blood cannot be simply transfused to every patient in need of transfusion. On the surface of red blood cells blood group antigens are present. When a recipient of a red blood cell transfusion has an antibody to a blood group antigen present on the transfused donor red blood cells, the immune system of the recipient can destroy all donor red blood cells, which results in a sometimes fatal transfusion reaction. Consequently, it is very important to transfuse compatible donor red blood cells to an immunized recipient. Blood group antigens In 1901, Landsteiner discovered that red blood cells of different healthy humans were not completely the same.1 He detected three differences on the membrane of red blood cells and named them A, B and O.1 Although intensive research was done to detect more blood group antigens, it took more than 25 years to discover another blood group antigen, the M antigen.2-4 The majority of blood group antigens were discovered after the development of the indirect antiglobulin test by Coombs et al. in 1945, which dramatically increases the sensitivity of serological blood group typing.2,5 At this moment more than 300 different blood group antigens are known, which are divided into thirty-three blood group systems, six blood group collections and two red blood cell antigen series (Table 1).6,7 It is expected that the Vel blood group, of which the genetic basis was recently elucidated, will be assigned as the 34 blood group system (Table 1). Blood group antigens are structures, proteins, carbohydrates or lipids, present on the membrane of red blood cells (Figure 1).6,8,9 Not all structures on the red blood cell membrane are blood group antigens.6,8,9 To be entitled as a blood group antigen, the antigen must be serologically characterized by human antibodies and the antigen must be inheritable.6,8,9 Origin of blood group antigens The huge variety of blood group antigens is thought to have arisen due to evolutionary pressure of various pathogens.10,11 The different antigens of the carbohydrate blood groups are assumed to originate from pressure of microbial pathogens.12,13 Parasitic pathogens such as malaria are responsible for differential expression of blood group antigens carried on protein 9 Chapter 1 structures.14,15 The effect of malaria on blood group antigen expression can still be observed via the geographic distribution of specific blood group phenotypes.14-16 For instance, in West- Africa almost 100% of the population lacks the complete expression of the Duffy glycoprotein, which makes them resistant for malaria infection by Plasmodium vivax.14,16 Nevertheless, for many blood group antigens the evolutionary pressure is not known and possibly even non existing. Differential blood group antigen expression might also be due to genetic drift, for many blood group antigens the geographic distribution can simply be explained by founder effects.17 Figure 1. Model of structures that carry blood group antigens on the red blood cell membrane. (modified from Reid et al. 2013; ref6). Molecular basis of blood group antigens The first blood group antigens for which the molecular basis was clarified were the M and N antigen, when Siebert and Fukuda cloned the GYPA gene in 1986.18 Due to the rapid evolvement of DNA techniques, the genetic basis of the majority of blood group antigens was elucidated in less than ten years.10,11,19 At this moment there are, however, still blood group antigens of which the genetic basis is not elucidated, for instance the Ata and Emm blood group antigens.6,9 Differential expression of blood group antigens can be due to single 10 Table 1. Overview of the 34 blood group systems, 6 blood group collections and 2 red blood cell antigen series ISBT ISBT name Number Chromo- Gene Anti- Frequency Genetic difference(s) between antigen 1 and antigen 2 Antigen 2 Frequency No of some loca- gen 1 of antigen of antigen antigens tion 1* 2* Blood group systems 1 ABO 4 9q34.1-q34.2 ABO A 47% c.297A>G† c.526C>G c.657C>T† c.703G>A c.796 c.803 c.930 B 13% C>A G>C G>A† 2 MNS 46 4q31.21 GYPA M 78% c.59C>T c.71G>A c.72T>G N 72% GYPB S 55% c.143C>T S 89% 3 P1PK 3 22q13.2 A4GALT P1 79% c.42C>T P2 21% 4 Rh 52 1p36.11 RHD D 83% Deletion of RHD‡ Null 17% phenotype RHCE C 68% c.48C>G c.178A>C c.201G>A c.203G>A c.307 c 80% T>C E 29% c.676C>G e 98% 5 Lutheran 20 19q13.32 LU Lua 8% c.230G>A Lub 99.8% 6 Kell 34 7q34 KEL K 9% c.578C>T k 99.8% Kpa 2% c.841C>T Kpb 100% 7 Lewis 6 19p13.3 FUT3 Lea 22% § Leb 72% 8 Duffy 5 1q23.2 DARC Fya 66% c.125G>A Fyb 83% 9 Kidd 3 18q12.3 SLC14A1 Jka 77% c.838G>A Jkb 74% 10 Diego 22 17q21.31 SLC4A1 Dia 0.01% c.2561C>T Dib 100% Wra <0.01% c.1972G>A Wrb 100% 11 Yt 2 7q22.1 ACHE Yta >99.8% c.1057C>A Ytb 8% 12 Xg 2 Xp22.33 PBDX Xga 89% / Not determined General introduction 66%** MIC2 CD99 100% Not determined Null Rare phenotype 13 Scianna 7 1p34.2 ERMAP Sc1 >99% c.169G>A Sc2 1% a b 11 14 Dombrock 8 12p12.3 ART4 Do 67% c.378C>T c.624T>C† c.793G>A Do 82% Chapter 1 Chapter 1 12 Table 1.