TY - JOUR
T1 - SMIM1 underlies the Vel blood group and influences red blood cell traits
AU - Cvejic, Ana
AU - Haer-Wigman, Lonneke
AU - Stephens, Jonathan C.
AU - Kostadima, Myrto
AU - Smethurst, Peter A.
AU - Frontini, Mattia
AU - Van Den Akker, Emile
AU - Bertone, Paul
AU - Bielczyk-Maczynska, Ewa
AU - Farrow, Samantha
AU - Fehrmann, Rudolf S.
AU - Gray, Alan
AU - De Haas, Masja
AU - Haver, Vincent G.
AU - Jordan, Gregory
AU - Karjalainen, Juha
AU - Kerstens, Hindrik H.
AU - Kiddle, Graham
AU - Lloyd-Jones, Heather
AU - Needs, Malcolm
AU - Poole, Joyce
AU - Soussan, Aicha Ait
AU - Rendon, Augusto
AU - Rieneck, Klaus
AU - Sambrook, Jennifer G.
AU - Schepers, Hein
AU - Silljé, Herman H.
AU - Sipos, Botond
AU - Swinkels, Dorine
AU - Tamuri, Asif U.
AU - Verweij, Niek
AU - Watkins, Nicholas A.
AU - Westra, Harm Jan
AU - Stemple, Derek
AU - Franke, Lude
AU - Soranzo, Nicole
AU - Stunnenberg, Hendrik G.
AU - Goldman, Nick
AU - Van Der Harst, Pim
AU - Van Der Schoot, C. Ellen
AU - Ouwehand, Willem H.
AU - Albers, Cornelis A.
N1 - Funding Information:
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).
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878539656&partnerID=8YFLogxK
U2 - 10.1038/ng.2603
DO - 10.1038/ng.2603
M3 - Article
C2 - 23563608
AN - SCOPUS:84878539656
SN - 1061-4036
VL - 45
SP - 542
EP - 545
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -