In this project we investigated the function of SMIM1, the recently characterized protein carrying the VEL blood group system. Anti-Vel antibodies can cause serious transfusion reactions. In previous research we obtained indications that SMIM1 might be a novel regulator of red blood cell (RBC) formation, because donors with lower amounts of SMIM1 had diminished RBC parameters. We have produced a monoclonal antibody specifically recognizing SMIM1. This reagent turned out to be very valuable for typing of blood bank donors, which was until now cumbersome. We were able to successfully implement Vel-typing in high throughput typing in the blood bank. This is relevant for allo-immunized Vel-negative patients who need a blood transfusion. SMIM1 was found to be expressed both on the membrane and the cytosol of erythroid cells, the membrane expression gradually increases when the erythroid cells mature. We characterized novel SMIM1 variants, in which mutations result in almost absent Vel-expression. We showed that this lowered expression mainly occurred during the final steps of maturation of erythroid cells, when the nuclei are expelled and the reticulocytes loose membranes when they transform into RBCs. To investigate the possible role of SMIM1 in RBC formation, we applied several approaches. SMIM1 is a highly conserved protein and also in zebrafishes the knock down of its orthologue resulted in anemia. We generated mice that were deficient for SMIM1. These mice did not show any abnormalities in RBC formation. To study the role in human RBC formation we analyzed the RBC formation in rare Vel-negative donors and in donors carrying naturally mutations in SMIM1 (so called Vel-weak donors), and also in human iPSC cell lines and hematopoietic progenitor cells that were made deficient for SMIM1. In none of these cells we observed any effect on RBC formation. We therefore concluded that the role of SMIM1 is redundant and not essential for murine or human RBC formation, and that no further research is warranted.

Thesis 2018: Beyond the rare blood group Vel, uncovering the functions of SMIM1 in blood and in other organs, Ana Tome