Impact of genetic variation in the <i>SMIM1</i> gene on Vel expression levels

Haer‐Wigman, Lonneke; Stegmann, Tamara C.; Solati, Shabnam; Soussan, Aïcha Ait; Beckers, Erik A.M.; Harst, Pim van der; Hulst-Sundermeijer, Marga van; Ligthart, Peter; Rhenen, Dick van; Schepers, Hein; Haas, Masja de; Schoot, C. Ellen van der

doi:10.1111/trf.13014

Cited by 19 publications

(67 citation statements)

References 16 publications

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“…Downregulation of all three genes was also confirmed in cross controls (Figure 5B). This finding is consistent with previous population-based studies that show an association between an LD block containing rs1175550 with whole blood SMIM1 mRNA expression and its surface protein expression on RBCs (Cvejic et al, 2013; Haer-Wigman et al, 2015). …”

Section: Resultssupporting

confidence: 93%

Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits

Ulirsch

Nandakumar

Wang

et al. 2016

Cell

306

386

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Summary Genome-wide association studies (GWAS) have successfully identified thousands of associations between common genetic variants and human disease phenotypes, but the majority of these variants are non-coding, often requiring genetic fine-mapping, epigenomic profiling, and individual reporter assays to delineate potential causal variants. We employ a massively parallel reporter assay (MPRA) to simultaneous screen 2756 variants in strong linkage-disequilibrium with 75 sentinel variants associated with red blood cell traits. We show that this assay identifies elements with endogenous erythroid regulatory activity. Across 23 sentinel variants, we conservatively identified 32 MPRA functional variants (MFVs). We demonstrate endogenous enhancer activity across 3 MFVs that predominantly affect the transcription of SMIM1, RBM38, and CD164 using targeted genome editing. Functional follow up of RBM38 delineates a key role for this gene in the alternative splicing program occurring during terminal erythropoiesis. Finally, we provide evidence for how common GWAS-nominated variants can disrupt cell-type specific transcriptional regulatory pathways.

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Section: Resultssupporting

confidence: 93%

Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits

Ulirsch

Nandakumar

Wang

et al. 2016

Cell

306

386

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“…Because anti-Vel sera of immunized patients mostly contain a high IgM fraction, the results in the ScanGel cards which were known to be very sensitive for IgM antibodies gave positive reactions with all heterozygous Vel samples even though the widely used ID cards were negative with some of them. Furthermore, genetic factors such as the rs1175550 SNP in the non-coding region of SMIM1 can affect the expression of the Vel antigen [6,7]. We could confirm the association of the minor G allele of rs1175550 with a significantly stronger antigen expression in 5 blood donors, who were presumably compound heterozygous for 64-80del and the rs1175550-G alleles.…”

Section: Discussionsupporting

confidence: 75%

“…The frequency of the SMIM1 64-80del allele of 1.81% in our study cohort corresponds to the observations of approximately 1.6% in other European populations [6,7]. The highest allele frequencies were reported for Scandinavian countries, e.g.…”

Section: Discussionsupporting

confidence: 65%

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Molecular Screening for Vel- Blood Donors in Southwestern Germany

Wieckhusen

Rink

Scharberg

et al. 2015

Transfus Med Hemother

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Background: The SMIM1 protein carries the Vel blood group antigen, and homozygosity for a 17 bp deletion in the coding region of the SMIM1 gene represents the molecular basis of the Vel- blood group phenotype. We developed PCR-based methods for typing the SMIM1 17 bp (64-80del) gene deletion and performed a molecular screening for the Vel- blood type in German blood donors. Methods: For SMIM1 genotyping, TaqMan-PCR and PCR-SSP methods were developed and validated using reference samples. Both methods were used for screening of donors with blood group O from southwestern Germany. Heterozygotes and homozygotes for the SMIM1 64-80del allele were serologically typed for the Vel blood group antigen. In addition, the rs1175550 SNP in SMIM1 was typed and correlated to the results of the phenotyping. Results: Both genotyping methods, TaqMan-PCR and PCR-SSP, represent reliable methods for the detection of the SMIM1 64-80del allele. Screening of 10,598 blood group O donors revealed 5 individuals homozygous for the deletional allele. They were confirmed Vel- by serological typing. Heterozygotes for the 64-80del allele showed different antigen expressions ranging from very weak to regular positive. Conclusion: Molecular screening of blood donors for the Vel- blood type is feasible and avoids the limitations of serological typing which might show false-negative results with heterozygous individuals. The identification of Vel- blood donors significantly contributes to the adequate blood supply of patients with anti-Vel.

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“…While some of the variation can be attributed to heterozygosity for the 17-bp deletion1, this mutation does not account for all the variation. The common SNP rs1175550 (A > G, minor allele frequency, MAF = 0.22 in Caucasians), located in intron 2 of SMIM1 , associates with mean corpuscular hemoglobin concentration (MCHC)4, and individuals who carry the minor allele (rs1175550G) express SMIM1 at a higher level than individuals who carry the major allele (rs1175550A)256. However, it is not known whether rs1175550 itself is causal, or a proxy for another (as yet undetected) causal variant.…”

mentioning

confidence: 99%

SMIM1 variants rs1175550 and rs143702418 independently modulate Vel blood group antigen expression

Christophersen

Jöud

Ajore

et al. 2017

Sci Rep

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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.

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Impact of genetic variation in the SMIM1 gene on Vel expression levels

Cited by 19 publications

References 16 publications

Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits

Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits

Molecular Screening for Vel- Blood Donors in Southwestern Germany

SMIM1 variants rs1175550 and rs143702418 independently modulate Vel blood group antigen expression

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