27.10.2022: Publication Alert - Missense mutations in PIEZO1, encoding the Piezo1 mechanosensor protein, define the Er red blood cell antigens
The occurrence of fatal HDFN associated with antibodies directed against Er antigens highlights their clinical relevance, elucidating another facet of the importance of Piezo1 in human biology.
Despite the identification of the high incidence red cell antigen Era nearly 40 years ago, the molecular background of this antigen, together with the other two members of the Er blood group collection, has yet to be elucidated. Whole exome and Sanger sequencing of individuals with serologically defined Er alloantibodies identified several missense mutations within the PIEZO1 gene, encoding amino acid substitutions within the extracellular domain of the Piezo1 mechanosensor ion channel. Confirmation of Piezo1 as the carrier molecule for the Er blood group antigens was demonstrated using immunoprecipitation, CRISPR/Cas9-mediated gene knockout and expression studies in an erythroblast cell line. We report the molecular bases of five Er blood group antigens: the recognised Era, Erb and Er3 antigens; and two novel high incidence Er antigens, described here as Er4 and Er5, establishing a new blood group system. Anti-Er4 and anti-Er5 are implicated in severe hemolytic disease of the fetus and newborn (HDFN). Demonstration of Piezo1, present at just a few hundred copies on the surface of the red blood cell, as the site of a new blood group system highlights the potential antigenicity of even low abundance membrane proteins and contributes to our understanding of the in vivo characteristics of this important and widely studied protein in transfusion biology and beyond.