Genetic Control of Splicing at SIRPG Modulates Risk of Type 1 Diabetes

Genetic Control of Splicing at SIRPG Modulates Risk of Type 1 Diabetes
james freeman diabetes freedom

Signal regulatory protein SIRP (CD172G) is expressed on the surface of lymphocytes where it acts by engaging its ligand, CD47. SIRPG, which encodes SIRP, contains a non-synonymous coding variant, rs6043409, which is significantly associated with risk for type 1 diabetes. SIRPG produces multiple transcript isoforms via alternative splicing, all encoding potentially functional proteins. We show that rs6043409 alters a predicted exonic splicing enhancer, resulting in significant shifts in the distribution of SIRPG transcript isoforms. All of these transcript isoforms produced protein upon transient expression in vitro. However, CRISPR targeting of one of the alternatively spliced exons in SIRPG eliminated all SIRP expression in Jurkat T cells. These targeted cells formed fewer cell-cell conjugates with each other than with wild type Jurkat cells, expressed reduced levels of genes associated with CD47 signaling and had significantly increased levels of cell surface CD47. In primary CD4+ and CD8+ T cells cell surface SIRP levels in response to anti-CD3 stimulation varied quantitatively by rs6043409 genotype. Our results suggest that SIRPG is the most likely causative gene for type 1 diabetes risk in the 20p13 region and highlight the role of alternative splicing in lymphocytes in mediating the genetic risk for autoimmunity.

Diabetes Journal publish ahead of print articles
Smith, M. J.; Pastor, L.; Newman, J. R. B.; Concannon, P.
james freeman diabetes freedom

Written by 

Leave a Reply

Your email address will not be published. Required fields are marked *