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

Ana Cvejic, Lonneke Haer-Wigman, Jonathan C Stephens, Myrto Kostadima, Peter A Smethurst, Mattia Frontini, Emile van den Akker, Paul Bertone, Ewa Bielczyk-Maczyńska, Samantha Farrow, Rudolf S N Fehrmann, Alan Gray, Masja de Haas, Vincent G Haver, Gregory Jordan, Juha Karjalainen, Hindrik H D Kerstens, Graham Kiddle, Heather Lloyd-Jones, Malcolm Needs, Joyce Poole, Aicha Ait Soussan, Augusto Rendon, Klaus Rieneck, Jennifer G Sambrook, Hein Schepers, Herman H W Silljé, Botond Sipos, Dorine Swinkels, Asif U Tamuri, Niek Verweij, Nicholas A Watkins, Harm-Jan Westra, Derek Stemple, Lude Franke, Nicole Soranzo, Hendrik G Stunnenberg, Nick Goldman, Pim van der Harst, C Ellen van der Schoot, Willem H Ouwehand, Cornelis A Albers

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.