Recent insights into human autoimmunity and immune tolerance have come from studies of rare monogenic disorders. For example, type 1 diabetes (T1D) and thyroid autoimmunity are frequent features in patients with mutations in AIRE and FOXP3. Dissecting the consequences of these mutations has improved our understanding of the role of central T cell tolerance and T regulatory cells in controlling these organ-specific autoimmune diseases. Over the last decade, rapid advances in genetic sequencing have now allowed for a deeper exploration and discovery of rare variants that are linked to disease with techniques like whole exome sequencing. Using this approach in both kindreds and outlier patients with de novo germline mutations, there has been expanding discovery of mutations in other pathways with a link to organ-specific autoimmunity that include STAT3, STAT1, CTLA4, and LRBA. Here, we utilized a similar approach on a single patient with T1D and other autoimmune and inflammatory conditions. We identified a de novo heterozygous c.457G>A/p.Gly153Arg mutation in the SKAP2 gene. SKAP2 encodes a critical mediator of integrin signaling pathways that regulate myeloid immune cell function. Monocyte-derived macrophages from the individual displayed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. We propose that SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, resulting in a break in immune tolerance and T1D. This particular mutation in a patient with T1D and multiple autoimmunity implicates a role for activating SKAP2 variants in autoimmune T1D.  

Disclosure

C. Chamberlain: None. N. Rutsch: None. W. Dixon: None. L. R. Letourneau-freiberg: None. L. H. Philipson: Advisory Panel; Self; Nevro Corp., Research Support; Self; Provention Bio, Inc. M. German: Stock/Shareholder; Self; Viacyte, Inc. M. S. Anderson: Consultant; Self; Provention Bio, Inc., VielaBio, Stock/Shareholder; Self; Medtronic, Merck & Co., Inc. C. A. Lowell: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D018); Larry L. Hillblom Foundation (2014-D-004-NET); University of California San Francisco Parnassus Flow Core (RRID:SCR_018206); National Institutes of Health (P30 DK063720, S101S10OD021822-01); German Research Foundation (ZA428/11-1, ZA428/18-1, INST211/604-1)

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