Beyond the rare blood group Vel, uncovering the functions of SMIM1 in blood and in other organs

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Ramalho Tomé, Ana Rita

Advisors dc:contributor.advisor

• Ouwehand, Willem H.
• Frontini, Mattia

• Blood groups
• Vel blood group system
• Red blood cells
• Platelets
• Megakaryocytes

Statement dc:rights

• Licensee: University of Cambridge Order Date: May 22, 2019 Order Number: 4594130618378 Publication: Cell Title: Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity Type of Use: reuse in a thesis/dissertation Licensee: University of Cambridge Order Date: May 22, 2019 Order Number: 4594130924519 Publication: Nature Genetics Title: Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype Type of Use: Thesis/Dissertation

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/8cc68357-3f7a-4dd9-9c33-b273036fe740/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

Author Identifier

0000-0002-4391-7762
0000-0002-7744-1790
0000-0001-8074-6299

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/293047