Rare cases of monogenic type 1 diabetes (T1D) represent defects in critical pathways of immune tolerance and autoimmune disease. We therefore identified and recruited patients with likely monogenic causes of T1D and performed next-generation sequencing to discover new candidate genes and mechanisms of disease. We discovered a large kindred with an autosomal dominant inheritance pattern of T1D, with all affected members positive for autoantibodies and the index patient also having inflammatory bowel disease. Whole exome sequencing analysis of six family members across three generations revealed a novel mutation in the interleukin-17 receptor C gene (IL17RC) that cosegregated with T1D and was predicted to be both damaging and rare. No other mutations were identified. IL17RC is broadly expressed and encodes a single-pass transmembrane receptor that mediates the inflammatory activities of Th17 cells. We found that cells expressing the mutant IL17RC did not ectopically activate IL-17 signaling but instead had a hyperactive response to the Th17 cytokine IL17A and other inflammatory signals. Our data identifies inflammatory signaling via IL17RC as an important and novel regulator of autoimmune diabetes in humans.
C. Chamberlain: None. J. Wang: None. S.E. Gitelman: Advisory Panel; Self; Avortes, Intermountain Therapeutics, Lilly Diabetes, Tolerion, Inc. Research Support; Self; Caladrius Biosciences, Inc., Janssen Research & Development. Other Relationship; Self; Novo Nordisk Inc. M. German: Advisory Panel; Self; Encellin. Stock/Shareholder; Self; Encellin, Viacyte, Inc. M.S. Anderson: None.
The Leona M. and Harry B. Helmsley Charitable Trust; Larry L. Hillblom Foundation; Nora Eccles Treadwell Foundation; National Institutes of Health