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Title: Beyond the rare blood group Vel, uncovering the functions of SMIM1 in blood and in other organs
Author: Ramalho Tomé, Ana Rita
ISNI:       0000 0004 7962 0367
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Vel is a universal antigen present on the red blood cells (RBCs) membrane, which defines the Vel-blood group system. The identification of Vel-encoding gene, SMIM1, suggested that this is a regulator of erythropoiesis. Its role in RBCs and potential role in other cells, however, remains largely unknown. Here, I aimed to characterise the role of SMIM1 in haematopoietic lineages and other organs by using two main approaches (in vivo and in vitro) and three models (human volunteers, mouse and cell lines). First, using available datasets, I showed that SMIM1 is expressed in megakaryocytes (MKs), platelets, neutrophils and naïve, memory and class-switched B-lymphocytes. I further demonstrated that SMIM1 localisation and the type of multimers it forms in some of those cells are cell type dependent. Second, I assessed the effect of the absence of SMIM1 in qualitative and quantitative blood traits in two human cohorts (Vel-negative blood donors recruited in this study and Vel-negative/weak individuals of the 400,000 UK Biobank study) and in a Smim1 mutant mouse model. Small but significant alterations were observed in RBC, platelets and neutrophils counts in Vel-negative individuals and Smim1 mutant mice, however, the directionality of these changes and their significance was model specific. Third, I investigated the role of SMIM1 in platelets formation and function. I showed that SMIM1 is phosphorylated during platelet activation in humans and its ablation in male mouse platelets leads to a reduction of P-selectin surface expression on resting platelets. These findings suggest a role for SMIM1 during platelet activation. Furthermore, I described a novel metabolic phenotype both in human and mouse SMIM1 knockouts. I showed that SMIM1 absence leads to an increase in body weight (and consequently in body mass index (BMI)) in male Vel-negative donors and female Smim1-/- mice. Altogether, these findings provide new insights into the role of SMIM1 and the biological processes it is involved, which may have the potential to reveal unknown clinical phenotypes related with SMIM1 ablation and to inform their prevention and treatment.
Supervisor: Ouwehand, Willem H. ; Frontini, Mattia Sponsor: Landsteiner Foundation for Blood Transfusion Research ; University of Cambridge
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Blood groups ; Vel blood group system ; Red blood cells ; Platelets ; Megakaryocytes