Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype

• DOI: 10.1038/ng.2600
• Publication Date: 2013-04-07T17:37:37Z
• Authors: Jill R Storry; Magnus Jöud; Mikael Kronborg C...; Britt Thuresson; Bo Åkerström; Birgitta Nilsson ...; Björn Nilsson; Martin L Olsson
• Keywords: Male; 0301 basic medicine; Infectious Medicine; Erythrocytes; Molecular Sequence Data; 03 medical and health sciences; 0302 clinical medicine; Isoantibodies; Animals; Humans; Exome; Gene Regulatory Networks; Amino Acid Sequence; Alleles; Genome, Human; Gene Expression Profiling; Erythrocyte Membrane; Homozygote; Membrane Proteins; Hematology; Flow Cytometry; 3. Good health; Blood Group Antigens; Female; Biomarkers; Gene Deletion

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.