A person’s blood type is determined by the presence or absence of proteins (blood groups)  present on the surface of red blood cells. Although ABO or Rh are most well-known, there are many other important blood groups. Where mismatch exists between one person’s blood and that of another, the possibility of alloimmunisation (the process by which a person generates an antibody against a blood group antigen that they do not carry) arises. The presence of alloantibodies can have clinical consequences in transfusion or pregnancy by triggering an attack by the immune system. 

Researchers from Bristol’s School of Biochemstry and NHSBT’s International Blood Group Reference Laboratory (IBGRL) spearheaded an international collaboration which sought to investigate a 30-year mystery surrounding the basis of three known, but genetically uncharacterised, antigens that did not fit into any known blood group system. 

In this study, individuals with alloantibodies against a collection of antigens termed Er, that were first observed more than 30-years ago, were investigated by applying a powerful technique allowing simultaneous analysis of all their gene coding DNA sequences. Specific changes were identified in the gene coding for the Piezo1 protein, which would result in the production of an altered protein on the cell surface of these individuals. Using gene editing in an immortalised cell-line developed in Bristol, the Piezo1 protein was first removed and then reintroduced to definitively prove that alloantibodies to Er antigens (including two never before reported) bind to Piezo1, and that Piezo1 is required for Er antigen expression. 

Using a combination of cutting-edge DNA sequencing and gene-editing techniques, the team were able to conclusively show that Piezo1, a protein of widespread biological interest, is the carrier for these sites (and more) and, in so doing, establish Er as a new blood group system. 

Piezo proteins are mechanosensory proteins that are used by the red cell to sense when its being squeezed. The protein is present at only a few hundred copies in the membrane of each cell. This study really highlights the potential antigenicity of even very lowly expressed proteins and their relevance for transfusion medicine. 

Read the full University of Bristol news item

Paper: 'Missense mutations in PIEZO1, encoding the Piezo1 mechanosensor protein, define the Er red blood cell antigens' by Vanja Karamatic Crew, Louise A Tilley, Timothy J Satchwell et al. in American Society of Hematology.