Abstract
Emm is a high incidence red cell antigen with eight previously reported Emm− probands. Anti-Emm appears to be naturally occurring yet responsible for a clinically significant acute hemolytic transfusion reaction. Previous work suggests that Emm is located on a GPI-anchored protein, but the antigenic epitope and genetic basis have been elusive. We investigated samples from a South Asian Indian family with two Emm− brothers by whole genome sequencing (WGS). Additionally, samples from four unrelated Emm− individuals were investigated for variants in the candidate gene. Filtering for homozygous variants found in the Emm− brothers and by gnomAD frequency of < 0.001 resulted in 1818 variants with one of high impact; a 2-bp deletion causing a frameshift and premature stop codon in PIGG [NM_001127178.3:c.2624_2625delTA, p.(Leu875*), rs771819481]. PIGG encodes for a transferase, GPI-ethanolaminephosphate transferase II, which adds ethanolamine phosphate (EtNP) to the second mannose in a GPI-anchor. The four additional unrelated Emm− individuals had various PIGG mutations; deletion of Exons 2–3, deletion of Exons 7–9, insertion/deletion (indel) in Exon 3, and new stop codon in Exon 5. The Emm− phenotype is associated with a rare deficiency of PIGG, potentially defining a new Emm blood group system composed of EtNP bound to mannose, part of the GPI-anchor. The results are consistent with the known PI-linked association of the Emm antigen, and may explain the production of the antibody in the absence of RBC transfusion. Any association with neurologic phenotypes requires further research.
Highlights
Emm is a high incidence red cell antigen with eight previously reported Emm− probands
We previously found by Western blot and hemagglutination that red blood cell (RBC) from Emm− individuals do not lack GPI-anchored acetylcholinesterase (ACHE, Yt blood group), complement decay-accelerating factor (CD55, Cromer blood group), ecto-ADP-ribosyltransferase 4 (ART4, Dombrock blood group), lymphocyte functionassociated antigen 3 (CD58), and CD59 glycoprotein (CD59, CD59 blood group)[4]
We show here, using family inheritance analysis and a genome wide search, that PIGG is responsible for the Emm blood group system
Summary
Emm is a high incidence red cell antigen with eight previously reported Emm− probands. Anti-Emm does not react with RBCs from individuals with paroxysmal nocturnal hemoglobinuria (PNH) type III, which lack glycosylphosphatidylinositol (GPI) anchored proteins, principally due to somatic mutation in phosphatidylinositol glycan A (PIGA)[7]. This observation suggested that Emm is located on a GPI-linked protein[4,8]. PIGG deletion mutations were present in samples from two additional unrelated probands of Japanese and European extraction previously investigated in our laboratory, and in two generations of a North African family with two sisters who had Emm− RBC phenotypes with anti-Emm identified during pregnancy. Two siblings reported previously and known to have loss of function PIGG mutations[11] were found to have Emm− RBC phenotypes
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