1462-P: ASCL1—A Potentially Novel Type 1 Diabetes Gene

Background: New insights into type 1 diabetes (T1D) have recently come from studies of rare monogenic forms of the disease. Uncovering the genes that drive these monogenic forms can reveal mechanisms and druggable pathways in affected families that may be extended to the general T1D population. We have identified one such candidate gene: Achaete-scute complex 1 (ASCL1). ASCL1 encodes a basic helix-loop-helix (bHLH) transcription factor and is well-known for its role in neurogenesis, however it is less understood how this gene may impact immune tolerance. Recent studies have demonstrated that ASCL1 and its targets are expressed in medullary thymic epithelial cells (mTECs), which are key players in the removal of autoreactive T cells from the thymus. Methods: Whole exome sequencing (WES) was performed on individuals from our monogenic T1D registry and functional studies were performed in a human cell line using lentiviral vectors and bulk RNAseq. Results: We identified a novel coding mutation in the bHLH transcription factor ASCL1 in siblings with suspected monogenic T1D. WES revealed a heterozygous coding variant in ASCL1 that was predicted to be both deleterious and rare. This caused an amino acid substitution within the transcriptional activation domain of the ASCL1 protein. RNAseq analysis showed a broad reduction in the activation of gene targets in cells expressing the ASCL1 patient mutation. Conclusion: ASCL1 may play a role in central tolerance and be a new candidate gene for T1D. Disclosure K.C.Lavelle: None. K.Yang: None. J.Wang: None. C.Chamberlain: None. M.German: Advisory Panel; Encellin, Inc., Stock/Shareholder; ViaCyte, Inc. Funding The Leona M. and Harry B. Helmsley Charitable Trust; Larry L. Hillblom Foundation; Nora Eccles Treadwell Foundation; National Institute of Diabetes and Digestive and Kidney Diseases