Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, Lund, Sweden.
Sci Rep. 2017 Jan 13;7:40451. doi: 10.1038/srep40451.
The Vel blood group antigen is expressed on the red blood cells of most individuals. Recently, we described that homozygosity for inactivating mutations in SMIM1 defines the rare Vel-negative phenotype. Still, Vel-positive individuals show great variability in Vel antigen expression, creating a risk for Vel blood typing errors and transfusion reactions. We fine-mapped the regulatory region located in SMIM1 intron 2 in Swedish blood donors, and observed a strong correlation between expression and rs1175550 as well as with a previously unreported tri-nucleotide insertion (rs143702418; C > CGCA). While the two variants are tightly linked in Caucasians, we separated their effects in African Americans, and found that rs1175550G and to a lesser extent rs143702418C independently increase SMIM1 and Vel antigen expression. Gel shift and luciferase assays indicate that both variants are transcriptionally active, and we identified binding of the transcription factor TAL1 as a potential mediator of the increased expression associated with rs1175550G. Our results provide insight into the regulatory logic of Vel antigen expression, and extend the set of markers for genetic Vel blood group typing.
Vel 血型抗原在大多数个体的红细胞上表达。最近，我们描述了 SMIM1 中的失活突变的纯合性定义了罕见的 Vel 阴性表型。然而，Vel 阳性个体的 Vel 抗原表达存在很大的变异性，这增加了 Vel 血型定型错误和输血反应的风险。我们在瑞典献血者中对位于 SMIM1 内含子 2 中的调控区进行了精细作图，观察到表达与 rs1175550 以及先前未报道的三核苷酸插入(rs143702418; C > CGCA)之间存在很强的相关性。虽然这两个变体在白种人中紧密连锁，但我们在非裔美国人中分离了它们的作用，发现 rs1175550G 以及在较小程度上 rs143702418C 独立地增加了 SMIM1 和 Vel 抗原的表达。凝胶迁移和荧光素酶报告基因分析表明，这两个变体均具有转录活性，并且我们鉴定出转录因子 TAL1 的结合是与 rs1175550G 相关的表达增加的潜在介导因子。我们的结果提供了对 Vel 抗原表达调控逻辑的深入了解，并扩展了用于遗传 Vel 血型分型的标记物集。
