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SMIM1 underlies the Vel blood group and influences red blood cell traits

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Abstract

The blood group Vel was discovered 60 years ago1, 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 Vel2. 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)3. 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.

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Figure 1: The SMIM1 gene encodes the Vel blood group antigen.
Figure 2: Common SNP rs1175550 is an eQTL for SMIM1 and is associated with RBC traits.
Figure 3: Zebrafish knockdown of smim1.

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Acknowledgements

We thank the individuals who participated in this study. We thank A. Rogers and I. Simeoni for performing enrichment for the exome sequencing. We thank S. Garner, K. Downes and W. Erber for support with blood cell flow cytometry and morphology, H. Moes, G. Mesander and R.J. van der Lei for help with cell sorting, J.J. Erich, A. van Loon and colleagues for collecting cord blood and P. Ligthart for help with immune hemagglutination. This study makes use of data generated by the UK10K Consortium, derived from samples from the TwinsUK cohort. A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org/. Vel-negative donors and those with weak Vel expression in England were enrolled via the Cambridge BioResource and the NIHR BioResource for Rare Diseases. Jointly, these resources have in excess of 10,000 research volunteers, and the resources are funded by the NIHR Cambridge Biomedical Research Centre. The study was supported by grants from the NIHR (RP-PG-0310-1002 to P.A.S., G.K. and W.H.O.), the British Heart Foundation (RG/09/12/28096 to C.A.A. and A.R.), the Wellcome Trust (084183/Z/07/Z and 082597/Z/07/Z to J.C.S. and A.C.), the Cambridge BioResource (H.L.-J. and J.G.S.), the European Commission (BluePrint grants, 201110-201603, 282510 to S.F., M.F., H.H.D.K., H.S. and W.H.O.), Bloddonorernes Forskningsfond Denmark (to K.R.), Cancer Research UK (C45041/A14953 to A.C.), EMBL (to P.B.), The Netherlands Organisation for Scientific Research (NWO VENI grant 916.761.70 to P.v.d.H., NWO VENI grant 916.111.05 to H.S. and NWO VENI grant 916.10.135 to L.F.), the Netherlands Genomics Initiative (Horizon Breakthrough grant 92519031 to L.F.), the European Community's Health Seventh Framework Programme (FP7; 259867 to L.F.), the Dutch Interuniversity Cardiology Institute Netherlands (ICIN) and the Landsteiner Foundation for Blood Transfusion Research (LSBR; grant 1133).

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Contributions

A.C. performed zebrafish knockdown and analysis of zebrafish gene sequence. L.H.-W. collected clinical cases with antibody to Vel and performed confirmatory Sanger sequencing and phenotyping by flow cytometry and hemagglutination. J.C.S. performed confirmatory Sanger sequencing and analyzed the genotyping data. M.K. and P.B. analyzed the RNA-seq data. P.A.S. performed SMIM1 transfection experiments. M.F. and S.F. performed isolation of precursor cells. B.S., G.J., A.U.T. and N.G. performed analysis of the evolutionary conservation of the SMIM family genes. A.A.S. performed genotyping. E.v.d.A. carried out erythroblast culture and transfection. E.B.-M. performed zebrafish knockdown experiments with input from D. Swinkels. H.S., H.H.W.S., V.G.H. and N.V. carried out cell culture experiments and performed EMSAs and transfection experiments and quantitative PCR for SMIM1. R.S.N.F., J.K., H.-J.W. and L.F. performed eQTL and gene ontology analyses. A.G., M.N., J.P., J.G.S., H.L.-J., K.R., N.A.W. and M.d.H. were responsible for the identification of Vel-negative individuals and those with weak Vel expression by typing >360,000 samples. H.H.D.K. performed RNA-seq with supervisory input from H.G.S., who leads and coordinates the BluePrint epigenome project. G.K. supervised exome sequencing. A.R. analyzed expression data from whole-genome expression arrays and RNA-seq. H.S. analyzed expression data and created vectors. D. Swinkels analyzed iron homeostasis and other relevant laboratory measurements. D. Stemple oversaw zebrafish experiments. N.S. provided access before publication to RBC GWAS meta-analysis results. P.v.d.H. performed analysis of eQTLs and expression data, constructed SMIM1 vectors and provided access before publication to RBC GWAS meta-analysis results. C.E.v.d.S. and W.H.O. designed the study. C.A.A. performed exome sequence, Sanger sequence, genetic and statistical analyses. A.C., L.H.-W., C.E.v.d.S., W.H.O. and C.A.A. wrote the manuscript.

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Correspondence to Ana Cvejic, Willem H Ouwehand or Cornelis A Albers.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–4 and Supplementary Figures 1–8 (PDF 1619 kb)

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Cvejic, A., Haer-Wigman, L., Stephens, J. et al. SMIM1 underlies the Vel blood group and influences red blood cell traits. Nat Genet 45, 542–545 (2013). https://doi.org/10.1038/ng.2603

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