title: SMIM1 underlies the Vel blood group and influences red blood cell traits.
abstract: The blood group Vel was discovered 60 years ago, but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel. To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 × 10(-15)). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.
authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, United Kingdom.
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authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research, 1066 CX, Amsterdam, The Netherlands.|Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, The Netherlands.
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authors.lastname: Haer-Wigman
authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
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authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
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authors.initials: PA
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
authors.forename: Mattia
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authors.affiliation: Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, The Netherlands.|Department of Hematopoiesis, Sanquin Research, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Emile
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authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
authors.forename: Ewa
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
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authors.affiliation: NHS Blood and Transplant, Tooting, London, SW17 0RB, United Kingdom.
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authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research, 1066 CX, Amsterdam, The Netherlands.|Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, The Netherlands.
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, 9700 RB, The Netherlands.
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
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authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research, 1066 CX, Amsterdam, The Netherlands.|Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, The Netherlands.
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authors.initials: AA
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.|MRC Biostatistics Unit, Institute of Public Health, Cambridge, CB2 0SR, United Kingdom.
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authors.affiliation: Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark.
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Experimental Hematology, Groningen, 9700 RB, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Stem Cell Biology, Groningen, 9700 RB, The Netherlands.
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authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, United Kingdom.
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authors.affiliation: EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, 9700 RB, The Netherlands.
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authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research, 1066 CX, Amsterdam, The Netherlands.|Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, The Netherlands.
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.
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authors.initials: WH
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authors.affiliation: Department of Haematology, University of Cambridge, CB2 0PT, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, United Kingdom.|NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, United Kingdom.|NHS Blood and Transplant, Cambridge, CB2 0PT, United Kingdom.|Department of Human Genetics, Radboud University Medical Centre, Nijmegen, 6500 HB, The Netherlands.
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mesh_terms: D000483:Alleles; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001789:Blood Group Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004910:Erythrocyte Membrane / Q000378:metabolism*; D004912:Erythrocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006720:Homozygote; D006801:Humans; D007518:Isoantibodies / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D040641:Quantitative Trait Loci; D015027:Zebrafish / Q000235:genetics
chemical_list: D015415:Biomarkers; D001789:Blood Group Antigens; D007518:Isoantibodies; D008565:Membrane Proteins
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