Genetic Control of Splicing at SIRPG Modulates Risk of Type 1 Diabetes.
In: Diabetes, Jg. 71 (2022-02-01), Heft 2, S. 350-358
Online
academicJournal
Zugriff:
Signal regulatory protein SIRPγ (CD172G) is expressed on the surface of lymphocytes, where it acts by engaging its ligand, CD47. SIRPG, which encodes SIRPγ, contains a nonsynonymous 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/Cas9 targeting of one of the alternatively spliced exons in SIRPG eliminated all SIRPγ 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 SIRPγ 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.
(© 2022 by the American Diabetes Association.)
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Genetic Control of Splicing at SIRPG Modulates Risk of Type 1 Diabetes.
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Autor/in / Beteiligte Person: | Smith, MJ ; Pastor, L ; Newman, JRB ; Concannon, P |
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Zeitschrift: | Diabetes, Jg. 71 (2022-02-01), Heft 2, S. 350-358 |
Veröffentlichung: | Alexandria, VA : American Diabetes Association ; <i>Original Publication</i>: [New York, American Diabetes Association], 2022 |
Medientyp: | academicJournal |
ISSN: | 1939-327X (electronic) |
DOI: | 10.2337/db21-0194 |
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