OR28-3 A Mutation in KCNK16 Segregating with Autosomal Dominant Non-Ketotic Diabetes Drastically Increases TALK-1 Membrane Current: A Novel Gene for MODY?

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes. Exome sequencing of a non-obese four-generation family with autosomal dominant non-ketotic antibody-negative diabetes, who were negative for mutations in known MODY genes, identified a novel coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) affecting a highly conserved base and predicted to be damaging. KCNK16 encodes TALK-1, a pancreatic β-cell potassium channel which modulates β-cell excitability, controlling Ca(2+) influx and insulin secretion. Activation of TALK-1 reduces insulin secretion. A coding gain-of-function variant in KCNK16 is associated with type 2 diabetes in multi-ethnic genome-wide association studies. Notably, TALK-1 is not sensitive to sulfonylureas. HEK-293 cells were transfected with either wild-type or Leu114Pro TALK-1 constructs using a CMV promoter and including P2A mCherry to enable confirmation of successful transfection. Whole cell cross-membrane voltage clamping, with voltage ramped from -120mV to 60mV, demonstrated a drastic increase in current with mutant TALK-1 compared to wild-type, consistent with marked gain-of-function and likely to reduce insulin secretion. Our data suggest that KCNK16 may be a novel MODY gene. If confirmed, this has therapeutic implications not only for these individuals but potentially for novel management of type 2 diabetes. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.