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

• DOI: 10.2337/dc20-2317
• Publication Date: 2021-06-25T16:55:13Z
• Authors: Niklas Rutsch; Chester E. Chambe...; Wesley Dixon; Lauren Spector; Lisa R. Letournea...; Wint W. Lwin; Louis H. Philipson; Alexander Zarbock; Karline Saintus; Juehu Wang; Michael S. German; Mark S. Anderson; Clifford A. Lowell
• Keywords: Proband; Immune Dysregulation; Exome; Genome-wide Association Study

OBJECTIVE Multiple genome-wide association studies 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 functional consequence of novel coding mutation in patient with T1D gain further insight into impacts immune tolerance. RESEARCH DESIGN AND METHODS We 24-year-old individual other autoimmune inflammatory conditions. The proband first-degree relatives were recruited for whole-exome sequencing. Functional protein variant performed using cell line primary myeloid cells collected from family members. RESULTS Sequencing de novo (c.457G>A, p.Gly153Arg) proband. Assays monocyte-derived macrophages revealed enhanced activity integrin pathways migratory phenotype absence chemokine stimulation, consistent p.Gly153Arg being constitutively active. variant, located well-conserved lipid-binding loop, induced similar phenotypes when expressed human macrophage line. is gain-of-function, pathogenic that disrupts function, likely resulting break tolerance T1D. CONCLUSIONS plays key role activation migration. This particular multiple conditions implicates activating variants