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

• DOI: 10.2337/figshare.14192315.v1
• Publication Date: 2021-06-16T21:55:43Z
• 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

<b>OBJECTIVE: </b>Multiple genome-wide association studies (GWAS) have identified a strong genetic linkage between the <i>SKAP2</i> locus and type 1 diabetes (T1D) but how this leads to disease remains obscure. Here, we characterized functional consequence of novel coding mutation in T1D patient gain further insight into impacts immune tolerance. <p><b> </b></p> <p><b>RESEARCH DESIGN AND METHODS: </b>We 24-year-old individual with 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.</p> <p><b>RESULTS: </b>Sequencing <i>de novo</i> (c.457G>A, p.Gly153Arg) proband. Assays monocyte-derived macrophages revealed enhanced activity integrin pathways migratory phenotype absence chemokine stimulation, consistent SKAP2 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.</p> <p><b>CONCLUSIONS: </b>SKAP2 plays key role activation migration. This particular multiple autoimmunity implicates activating variants T1D. <br> </p>