Thesis defense Marea van der Rijst

On 17 February 2021 (14:00 hrs) Marea van der Rijst defended her thesis '"On the variation of SMIM1 expression |noVel insights in erythrocytes and during erythropoiesis"

Promotor:
Prof CE van der Schoot MD PhD

Copromotor:
E van den Akker PhD

Venue:
University of Amsterdam, online

Summary

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 aiding 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 Vel antigen expression during erythropoiesis.