Multiple ABCC8 Loss-of-Function Mutations Associated with Paradoxical Maturity-Onset Diabetes of the Young

ATP-sensitive potassium (KATP) channels, composed of SUR1 and Kir6.2 subunits, encoded by the ABCC8 and KCNJ11 genes, are critical regulators of membrane excitability and insulin secretion in pancreatic β-cells. A large number of ABCC8 and KCNJ11 missense variants have been identified in patients diagnosed with maturity-onset diabetes of the young (MODY), but the mechanistic link between these KATP variants and MODY remains quite unclear. As novel genetic variants do not often undergo functional characterization, there is confusion in the clinical literature as to whether the diabetes could be a late diagnosis of neonatal diabetes mellitus (NDM) caused by gain-of-function (GOF) mutations, or caused by loss-of-function (LOF) mutations that may initially manifest as hyperinsulinism and then cross over to diabetes. Here, we functionally characterized 16 ABCC8 variants previously reported as carried by patients diagnosed with MODY, most without an earlier diagnosis of hyperinsulinism, and traceable genetic inheritance. We demonstrate that 13 of 16 mutations cause an LOF of expressed SUR1/Kir6.2 KATP channels, 3 of 16 have no effect on channel activity (and are therefore presumably benign missense variants), and none causes KATP channel GOF. Together with other isolated cases reported by us and other groups, this solidifies the conclusion that KATP LOF can be associated with later-onset diabetes, and that it is inaccurate to assume that MODY-associated ABCC8 variants must induce KATP (GOF) or, therefore, that KATP inhibitors are appropriate treatment for this condition.