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

Nat Genet. 2013 May;45(5):542-545. doi: 10.1038/ng.2603. Epub 2013 Apr 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Biomarkers / metabolism
  • Blood Group Antigens / genetics*
  • Blood Group Antigens / immunology
  • Blood Group Antigens / metabolism
  • Electrophoretic Mobility Shift Assay
  • Erythrocyte Membrane / metabolism*
  • Erythrocytes / immunology*
  • Erythrocytes / metabolism
  • Erythrocytes / pathology
  • Exome / genetics
  • Female
  • Gene Deletion*
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Homozygote*
  • Humans
  • Isoantibodies / immunology
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Pregnancy
  • Quantitative Trait Loci*
  • Zebrafish / genetics


  • Biomarkers
  • Blood Group Antigens
  • Isoantibodies
  • Membrane Proteins