Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum-encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), where they bind to RBCs--preferentially of blood group A--to form large rosettes and mediate microvascular binding of iRBCs. We suggest that RIFINs have a fundamental role in the development of severe malaria and thereby contribute to the varying global distribution of ABO blood groups in the human population.

Key Points We extracted 210 412 blood group alleles (∼8.5 × 109 bp) from 1000 Genomes and matched them against official blood group reference lists. Of 1241 nonsynonymous variants found, 241 are known blood group polymorphisms while 1000 may represent undiscovered or altered antigens.

The Vel antigen is present on red blood cells (RBCs) from all humans except rare Vel-negative individuals who can form antibodies to Vel in response to transfusion or pregnancy. These antibodies may cause severe hemolytic reactions in blood recipients. We combined SNP profiling and transcriptional network modeling to link the Vel-negative phenotype to SMIM1, located in a 97-kb haplotype block on chromosome 1p36. This gene encodes a previously undiscovered, evolutionarily conserved transmembrane protein expressed on RBCs. Notably, 35 of 35 Vel-negative individuals were homozygous for a frameshift deletion of 17 bp in exon 3. Functional studies using antibodies raised against SMIM1 peptides confirmed a null phenotype in RBC membranes, and SMIM1 overexpression induced Vel expression. Genotype screening estimated that ~1 of 17 Swedish blood donors is a heterozygous deletion carrier and ~1 of 1,200 is a homozygous deletion knockout and enabled identification of Vel-negative donors. Our results establish SMIM1 as a new erythroid gene and Vel as a new blood group system.

Key Points• A new histo-blood group system was discovered, based on the identification of Forssman glycolipid antigen on human red blood cells.• A newly described polymorphism in the GBGT1 gene activates the encoded enzyme to synthesize Forssman antigen. IntroductionCarbohydrate histo-blood group antigens, first recognized on red blood cells (RBCs) in 1900, 1 have been suggested to be part of our innate immune response. 2 Major carbohydrate histo-blood groups in man include the ABO, P1PK, H, Lewis, I, and GLOB systems in which glycoproteins and glycolipids carry immunodominant terminal sugars, 3 defining polymorphic antigens. Other mammals also express carbohydrate histo-blood groups, such as ABO, 4 fucoseless B antigen (Galili), 5 and Forssman (Fs) 6,7 but their expression on RBCs varies among species. Although the biologic function of polymorphic carbohydrates on RBCs is unresolved, these antigens can be used as receptors by pathogens [8][9][10][11] and their expression in tissues and bodily secretions are thus believed to reflect microbial selection. 8 In response to blood-group-mimicking glycans on bacterial surfaces, naturally occurring antibodies with the capacity to neutralize various microorganisms are formed. However, these antibodies also constitute substantial transfusion and transplantation barriers. 3,12 In 1987, 3 families with a supposed ABO subgroup named A pae were reported. 13 Although Helix pomatia lectin reacted strongly and polyclonal anti-A weakly with RBCs from some family members, monoclonal (MAb) anti-A reagents were later shown to be nonreactive, thus presenting an apparent paradox. The biochemical and genetic background of this enigmatic phenotype has remained unknown, as has its biologic consequences. We hypothesized that an explanation may be found by studying the glycolipids of this phenotype. 14 Here we report the identification of Fs glycolipids, normally found only on RBCs of selected nonprimate mammals, are strongly expressed on human A pae RBCs. In nonprimates, Fs antigen is synthesized by Fs synthase (globoside 3-␣-N-acetyl-D-galactosaminyltransferase, EC2.4.1.88), 7 an enzyme homologous to the ABO transferase. We also reveal a genetic polymorphism in the human Fs gene (GBGT1) that alters the enzymatically inactive human protein 15 Methods SamplesFive and 3 RBC units were collected from each of 2 unrelated A pae individuals (A pae #1 and A pae #2, respectively) from 2 of the originally reported families. 13 GlycolipidsGlycolipid preparation. Lysed blood units were thawed and total neutral glycolipids with Ͻ 20 sugar residues were isolated (see supplemental Methods, where control glycolipid preparations are also described; available on the Blood Web site; see the Supplemental Materials link at the top of the online article).Open-column chromatography. Total glycolipids (ϳ 110 mg) from each of A pae #1 and #2 were fractionated by silica chromatography column (5g silica/100 mg lipid; Silica 60, Merck) in a system of chloroform (C) methanol (M) solvent mixes (supplemental Metho...

The S-s-U+var phenotype arises from changes in or around GYPB exon 5. The weak expression of U and in most examples, He, may be due to low levels of normal transcription of the variant gene or to posttranscriptional down regulation.