SKAP2-Manuscript-DC-SUPP-022421.pdf (1.37 MB)

Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation

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posted on 16.06.2021, 21:55 by Niklas Rutsch, Chester E. Chamberlain, Wesley Dixon, Lauren Spector, Lisa R. Letourneau-Freiberg, Wint W. Lwin, Louis H. Philipson, Alexander Zarbock, Karline Saintus, Juehu Wang, Michael S. German, Mark S. Anderson, Clifford A. Lowell
OBJECTIVE: Multiple genome-wide association studies (GWAS) have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D) but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a T1D patient to gain further insight into how this impacts immune tolerance.

RESEARCH DESIGN AND METHODS: We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members.

RESULTS: Sequencing identified a de novo SKAP2 variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed 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. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D.

CONCLUSIONS: SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmunity implicates a role for activating SKAP2 variants in autoimmune T1D.


This work was supported by the Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D018, G-2003-04376), the Larry L. Hillblom Foundation (2014-D-004-NET), the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01 DK104942, P30 DK020595), UCSF Parnassus Flow Core RRID:SCR_018206, DRC Center Grant NIH P30 DK063720, NIH S10 1S10OD021822-01 and a private donor. Alexander Zarbock was supported by the German research foundation (ZA428/11-1; ZA428/18-1; INST 211/604-1).