Disruption of SMIM1 causes the Vel− blood type

Abstract

Abstract Here, we report the biochemical and genetic basis of the Vel blood group antigen, which has been a vexing mystery for decades, especially as anti‐Vel regularly causes severe haemolytic transfusion reactions. The protein carrying the Vel blood group antigen was biochemically purified from red blood cell membranes. Mass spectrometry‐based de novo peptide sequencing identified this protein to be small integral membrane protein 1 (SMIM1), a previously uncharacterized single‐pass membrane protein. Expression of SMIM1 cDNA in Vel− cultured cells generated anti‐Vel cell surface reactivity, confirming that SMIM1 encoded the Vel blood group antigen. A cohort of 70 Vel− individuals was found to be uniformly homozygous for a 17 nucleotide deletion in the coding sequence of SMIM1. The genetic homogeneity of the Vel− blood type, likely having a common origin, facilitated the development of two highly specific DNA‐based tests for rapid Vel genotyping, which can be easily integrated into blood group genotyping platforms. These results answer a 60‐year‐old riddle and provide tools of immediate assistance to all clinicians involved in the care of Vel− patients.

Keywords

• blood group
• genotyping
• mass spectrometry
• membrane protein
• Vel