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

Abstract

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.

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Figure 1: Genome-wide SNP profiling maps the locus of the Vel-negative phenotype to chromosome 1p36.
Figure 2: Identification of SMIM1 as a previously uncharacterized transmembrane protein expressed in erythroid cells.
Figure 3: Founder mutation in SMIM1 explains a null phenotype in Vel-positive RBC membranes.
Figure 4: Confirmation of SMIM1 as the gene underlying Vel expression.
Figure 5: Enzymatic characterization of the extracellular domain of SMIM1.

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NCBI Reference Sequence

Referenced accessions

Gene Expression Omnibus

NCBI Reference Sequence

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Acknowledgements

We thank J. Poole, J. Hamilton, H. Hustinx and the Serum, Cells and Rare Fluids (SCARF) exchange scheme for kindly providing samples for this study. We thank J. Adolfsson, L. Järvstråt and A. Hult for technical assistance. We are indebted to the individuals and their families who participated in this project. The study was supported by research grants from the Swedish Foundation for Strategic Research (ICA08-0057 to B.N.), the Swedish Research Council (14251 to M.L.O.), governmental Avtal om Läkarutbildning och Forskning (ALF) grants to the University and Regional Laboratories (Labmedicin Skåne; to J.R.S., M.J., B.N. and M.L.O.), the Medical Faculty at Lund University (B.N. and M.L.O.), the Skåne County Council's Research and Development foundation, Sweden (M.L.O.), The Crafoord Foundation (J.R.S.), Marianne and Marcus Wallenberg's Foundation (2010.0112 to B.N.), Harald Jeansson's Foundation (B.N.), the Swedish Society of Medicine (B.N.), the National Blood Foundation of the American Association of Blood Banks (J.R.S.) and Glashofs Legat (302499 to M.K.C.).

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Contributions

J.R.S., B.N. and M.L.O. conceived, designed and coordinated the study. M.J. and B.N. performed genomic, bioinformatics and computational analyses. J.R.S. performed DNA sequence analysis and protein chemistry. B.T. designed and M.K.C. performed RACE, qPCR and overexpression experiments. J.R.S. and M.K.C. performed FACS analysis. B.N.S. contributed background knowledge, performed serological screening and enrolled blood donors. B.Å. contributed to experimental design and the early conception of the project. J.R.S., M.J., B.N. and M.L.O. discovered the 17-bp deletion in SMIM1 and wrote the manuscript. All authors contributed to the final manuscript.

Corresponding authors

Correspondence to Jill R Storry, Björn Nilsson or Martin L Olsson.

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Competing interests

A patent application covering Vel typing using genetic information from SMIM1 has been filed (J.R.S., M.J., B.N. and M.L.O.).

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Supplementary Tables 1–8 and Supplementary Figures 1–9 (PDF 752 kb)

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Storry, J., Jöud, M., Christophersen, M. et al. Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype. Nat Genet 45, 537–541 (2013). https://doi.org/10.1038/ng.2600

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