1. SMIM1 underlies the Vel blood group and influences red blood cell traits
- Author
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Dorine W. Swinkels, Heather Lloyd-Jones, Hendrik G. Stunnenberg, Graham Kiddle, Hindrik H. D. Kerstens, Gregory E. Jordan, Lonneke Haer-Wigman, Rudolf S N Fehrmann, Juha Karjalainen, Herman H W Silljé, Peter A. Smethurst, Cornelis A. Albers, Harm-Jan Westra, Hein Schepers, Jonathan Stephens, J. Poole, Willem H. Ouwehand, Mattia Frontini, Derek L. Stemple, Nicole Soranzo, Nicholas A. Watkins, Niek Verweij, Samantha Farrow, Augusto Rendon, Emile van den Akker, Vincent G. Haver, Alan Gray, C. Ellen van der Schoot, Ana Cvejic, Jennifer G. Sambrook, Myrto Kostadima, Nick Goldman, Ewa Bielczyk-Maczyńska, Botond Sipos, Malcolm Needs, Asif U. Tamuri, Aicha Ait Soussan, Lude Franke, Klaus Rieneck, Paul Bertone, Pim van der Harst, Masja de Haas, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Landsteiner Laboratory, and Clinical Haematology
- Subjects
Erythrocytes ,Molecular Sequence Data ,Quantitative Trait Loci ,Iron metabolism Pathogenesis and modulation of inflammation [IGMD 7] ,GENOMES ,Electrophoretic Mobility Shift Assay ,030204 cardiovascular system & hematology ,Biology ,VARIANTS ,Article ,Frameshift mutation ,Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3] ,03 medical and health sciences ,0302 clinical medicine ,Isoantibodies ,Pregnancy ,Gene expression ,Genetics ,medicine ,Animals ,Humans ,Exome ,Gene Regulatory Networks ,Allele ,Gene ,Molecular Biology ,Alleles ,Zebrafish ,030304 developmental biology ,Oligonucleotide Array Sequence Analysis ,GENE-EXPRESSION ,0303 health sciences ,Gene knockdown ,Gene Expression Profiling ,Erythrocyte Membrane ,Homozygote ,Membrane Proteins ,Molecular biology ,3. Good health ,Gene expression profiling ,Red blood cell ,ALIGNMENT ,medicine.anatomical_structure ,biology.protein ,Blood Group Antigens ,Female ,Antibody ,Biomarkers ,Gene Deletion - Abstract
The blood group Vel was discovered 60 years ago(1), 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(2). 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 x 10(-15))(3). 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.
- Published
- 2013