- Author
-
M.V.E. van der Rijst
- Title
- On the variation of SMIM1 expression
- Subtitle
- noVel insights in erythrocytes and during erythropoiesis
- Supervisors
-
C.E. van der Schoot
- Co-supervisors
-
E. van den Akker
- Award date
- 17 February 2021
- Number of pages
- 162
- ISBN
- 9789463615068
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
The genetic background of the Vel blood group has been a mystery for decades. Identifying SMIM1, SMall Integral Membrane protein 1, as the protein encoding the Vel antigen has significantly improved the identification of Vel negative donors. These rare donors are essential for safe blood transfusions. Current serological screening, however, encounters difficulties in accurately typing for the Vel antigen due to variable Vel antigen expression.
This thesis describes the production of a recombinant anti-Vel IgM antibody. This unlimited available antibody is capable of discriminating between Vel weak and Vel negative donors and thereby improves diagnostics in correctly typing for the Vel blood group. It describes the identification and characterization of a novel heterozygous missense mutation in SMIM1, which results in very weak Vel expression on red blood cells. The potential dominant negative effect of the currently known missense mutations in SMIM1 on wild type SMIM1 is investigated during erythropoiesis and reticulocyte maturation. It shows a significant loss of Vel expression during enucleation and reticulocyte maturation, resulting in nearly absence of the Vel blood group on red blood cells. It describes serine phosphorylation of SMIM1 to regulate SMIM1 protein levels during erythropoiesis. Additionally, it shows a possible role for SMIM1 conformation/multimerization within the membrane in Vel-positive individuals for the increased Vel antigen recognition during terminal differentiation. Combined, these observations provide building blocks for understanding the variable Vel antigen expression among individuals, during erythropoiesis. - Persistent Identifier
- https://hdl.handle.net/11245.1/28941e8b-9c77-4ba2-99e9-cb5274161bd7
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction and scope of thesis
Chapter 2: Development of a recombinant anti-Vel immunoglobulin M to identify Vel-negative donors
Chapter 3: Identification of a novel single-nucleotide mutation in SMIM1 gene that results in low Vel antigen expression
Chapter 4: SMIM1 missense mutations exert their effect on wild type Vel expression late in erythroid differentiation
Chapter 5: SMIM1 serine phosphorylation regulates SMIM1 protein levels during erythroid differentiation
Chapter 6: General discussion
Summary; Samenvatting; List of publications; PhD portfolio; Acknowledgements; Curriculum vitae
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