Disruption of SMIM1 causes the Vel− blood type

Bryan A Ballif,Thierry Peyrard,Sébastien Bourgouin,Virginie Helias,Cécile Menanteau,Carole Saison,Nicole Lucien,Maude Le Gall,Lionel Arnaud,Jean‐Pierre Cartron

doi:10.1002/emmm.201302466

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.

Highlights

Blood types are defined by the presence or absence of specific antigens at the surface of red blood cells (RBCs) and are inherited characters that result from genetic polymorphisms at different loci (Daniels, 2009)
Using a biochemical approach complemented with a genetic study, we have identified the molecular basis of the long soughtafter Vel blood group antigen
We found the Vel antigen to be carried by small integral membrane protein 1 (SMIM1) on RBCs

Summary

Introduction

Blood types are defined by the presence or absence of specific antigens at the surface of red blood cells (RBCs) and are inherited characters that result from genetic polymorphisms at different loci (Daniels, 2009). The Vel antigen is expressed on the RBCs of most people so that Sussman and Miller identified only four individuals whose RBCs did not react with the serum of Mrs ‘Vel’ by screening 10,000 blood donors with the O blood type from New York city (Sussman & Miller, 1952). This frequency of 0.0004 for individuals lacking the Vel antigen was confirmed by several large studies conducted in different parts of the world (Daniels, 2002), even though regional differences exist.

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Results

Conclusion