The Vel blood group system is defined by the presence of the Vel antigen on red blood cells. Vel is a high frequency antigen that shows variable strength, ranging from strong to weak. The rare Vel-negative blood type ... The Vel blood group system is defined by the presence of the Vel antigen on red blood cells. Vel is a high frequency antigen that shows variable strength, ranging from strong to weak. The rare Vel-negative blood type is inherited as an autosomal recessive trait and is typically unveiled when Vel-negative individuals develop anti-Vel antibodies after transfusion or pregnancy; Vel alloantibodies are never 'naturally occurring.' Individuals with anti-Vel antibodies may develop severe acute hemolytic transfusion reactions when transfused with Vel-positive blood. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel (summary by Daniels, 2002; Storry et al., 2013; Cvejic et al., 2013; Ballif et al., 2013).
Sussman and Miller (1952) first described the Vel-negative blood group phenotype in a 66-year-old woman who developed a severe acute intravascular hemolytic episode after a blood transfusion due to antibodies against a newly defined antigen named 'Vel.' She ... Sussman and Miller (1952) first described the Vel-negative blood group phenotype in a 66-year-old woman who developed a severe acute intravascular hemolytic episode after a blood transfusion due to antibodies against a newly defined antigen named 'Vel.' She had a history of 3 pregnancies and colon cancer requiring transfusions. Levine et al. (1961) reported a family in which 7 individuals spanning 3 generations were negative for the Vel red blood cell antigen. The proband was a woman who had been pregnant 6 times and received blood transfusions at least twice. She developed a severe transfusion reaction and was found to carry the Vel antibody in her serum, whereas her red cells lacked the Vel antigen. The other Vel-negative family members did not have serum anti-Vel antibodies. Subsequent reports of hemolytic reactions after transfusion of Vel-positive RBCs to Vel-negative individuals with antibody to Vel, as well as hemolytic disease of the newborns of Vel-negative mothers, established Vel as a clinically important blood group antigen (summary by Storry et al., 2013).
By SNP mapping followed by candidate gene sequencing of 20 Vel-negative individuals, Storry et al. (2013) identified a homozygous 17-bp deletion in the SMIM1 gene (615242.0001) in all individuals. The findings were confirmed in 15 additional Vel-negative individuals, ... By SNP mapping followed by candidate gene sequencing of 20 Vel-negative individuals, Storry et al. (2013) identified a homozygous 17-bp deletion in the SMIM1 gene (615242.0001) in all individuals. The findings were confirmed in 15 additional Vel-negative individuals, predominantly of European descent. Direct genotyping identified 30 heterozygous deletion carriers among 520 Swedish blood donors. The deletion was not found in the 1000 Genomes Project data, but was found in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) database: 57 of 5,763 European Americans and 6 of 3,198 in African Americans, yielding heterozygote frequencies of about 1 in 50 and 1 in 267, respectively. By exome sequencing of 5 individuals negative for the Vel antigen, Cvejic et al. (2013) found that 4 were homozygous and 1 was heterozygous for a 17-bp frameshift deletion in the SMIM1 gene. Combined with a follow-up study of additional Vel-negative individuals, a total of 63 of 69 Vel-negative individuals were found to be homozygous for the deletion. Five individuals classified as Vel-negative were heterozygous for the deletion and 1 was heterozygous for a missense mutation (M51R) only. Heterozygosity for the null allele in these individuals is most likely explained by misclassification of extremely weak Vel expression as Vel-negative. In addition, 19 of 20 individuals with weak Vel expression were heterozygous for the deletion. One individual with weak expression was heterozygous for a missense mutation (M51K). The 2 missense mutations may lead to inability of the SMIM1 protein to incorporate in the membrane, or may modify the epitope, leading to decreased binding of the antibody. Functional studies were not performed on the M51R or M51K variants. Expression of the Vel antigen on SMIM1-transfected HEK293T cells confirmed that SMIM1 is the gene underlying the Vel blood group. All 24 Vel-negative individuals or those with weak Vel expression who were heterozygous for the deletion were homozygous for the major A allele of SNP dbSNP rs1175550, which is present in intron 2 of the STIM1 gene and is associated with decreased SMIM1 transcript levels. The findings suggested that this SNP contributes to variable expression of the Vel antigen. Ballif et al. (2013) simultaneously identified the homozygous 17-bp deletion in the SMIM1 gene as the genetic basis for the Vel-negative blood group. Heterozygosity for the deletion was associated with weak Vel expression, consistent with a dosage effect. A common origin for the deletion was apparent.
Population studies estimate the prevalence of Vel-negative individuals at 1 in 4,000 in Europe, with a slightly higher prevalence in northern Scandinavia (1 in 1,700) (summary by Storry et al., 2013).