Gain of Function Mutation in SKAP2 Leading to Autoimmune Diabetes
Wednesday, June 22, 2022
4:15 PM – 4:30 PM PT
Location: Salons 1/2
Authors: Courtney Tamaki, BS (Co-Author) - University of California, San Francisco; Chester Chamberlain, PhD (Co-Author) - University of California, San Francisco; Jennifer Smith, PhD (Co-Author) - University of California, San Francisco; Lauren Spector, BS (Co-Author) - University of California, San Francisco; Niklas Rutsch, BS (Co-Author) - University of California, San Francisco; Wesley Dixon, BS (Co-Author) - University of California, San Francisco; Lisa Letourneau-Freiberg, MPH, RD (Co-Author) - University of Chicago; Lou Philipson, MD-PhD (Co-Author) - University of Chicago; Michael German, MD (Co-Author) - University of California, San Francisco; Mark Anderson, MD-PhD (Co-Author) - University of California, San Francisco; Clifford Lowell, MD-PhD (Presenting Author) - University of California, San Francisco
Institute of Medical Immunology, Charité Universitätsmedizin Berlin Berlin, Berlin, Germany
The study of the genetic basis for type 1 diabetes (T1D) has benefited tremendously from examination of rare individuals with likely monogenic forms of the disease. Using whole exome sequencing of individuals with T1D enrolled in a monogenic diabetes registry, we identified an individual with a gain-of-function mutation (G153R) in the SKAP2 gene.This individual also has multiple other autoimmune manifestations.Multiple GWAS studies have identified a strong genetic linkage between SKAP2 polymorphisms and T1D, however the mechanisms by which alteration of SKAP2 could lead to autoimmune T1D are unknown.SKAP2 is expressed primarily in myeloid cells, where it functions as an adapter protein in the integrin signaling pathway, linking cell surface integrins to actin rearrangements that occur following leukocyte adhesion. The SKAP2 G153R mutation resulted in a hyperadhesive phenotype in macrophagescultured from the patient.Knock-in (KI) mice containing the G153R substitution in murine Skap2, on the NOD genetic background, developed accelerated diabetes with histologic evidence of increased myeloid cell invasion of pancreatic islets.Female NOD.SKAP2 KI mice also have high levels ofautoantibodies to a wide range of tissue antigens, consistent with increased systemic autoimmunity.Neutrophils from G153R KI mice had increased integrin signaling while dendritic cells from these animals showed increased antigen presentation capacity to islet-specific transgenic T-cells.This study suggests that hyperactive integrin signaling in myeloid cells can drive autoimmunity, including type 1 diabetes.
