Missense mutations in PIEZO1, which encodes the Piezo1 mechanosensor protein, define Er red blood cell antigens

Abstract

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.

PIEZO Ion Channels in Cardiovascular Functions and Diseases

“…Thus, and despite its relatively low abundance in RBC membranes, 122 PIEZO1 was shown to be the genetic carrier of the Er blood group system. 148 The discovery of the genetic basis of the Er blood group should allow to develop new tests to identify individuals with this rare blood group, with the aim of providing better care to patients.…”

Pleiotropic physiological functions of Piezo1 in human body and its effect on malignant behavior of tumors

“…In addition, mutations in the Piezo1 gene are closely related to the occurrence and development of type B marine anemia by affecting red blood cell function ( Pinto et al, 2023 ). Because Piezo1 is the carrier of Er antigen, Piezo1 mutation is closely related to Er red blood cell antigen, which may explain Piezo1’s connection to neonatal hemolytic anemia ( Karamatic et al, 2023 ). Interestingly, Piezo1 is related not only to anemia but also to the prevention of malaria.…”

Piezo1 and Its Function in Different Blood Cell Lineages

“…Finally, Piezo1 was also proposed to have a role in controlling Er antigen expression in erythrocytes. Studies of individuals with alloantibodies against the Er antigen associated with a missense mutation in the Piezo1 gene led to the discovery that Piezo1 is required for Er antigen expression and established Er as a new blood group system [ 91 ].…”