A KCNJ11 mutation in the ATP-binding site of the KATP channel causes neonatal diabetes with epilepsy.

Background and Aims: ATP-sensitive K+ (KATP) channels link cell metabolism to electrical excitability of the plasma membrane. They are widely expressed in endocrine cells, heart, skeletal muscle, peripheral nerve and brain and play diverse roles in insulin secretion, neuronal excitability, cardiac stress and the response to cardiac and cerebral ischemia. They comprise pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits.Metabolic regulation is mediated by changes in intracellular adenine nucleotides. ATP binding to Kir6.2 inhibits KATP channel activity, and interaction of Mg-nucleotides with SUR increases channel activity: thus in the presence of MgATP, channel activity reflects a balance between these inhibitory and stimulatory actions. Heterozygous (het) mutations in Kir6.2 (KCNJ11) cause permanent neonatal diabetes either alone (PNDM) or in association with developmental delay, muscle weakness, and epilepsy (DEND syndrome). All mutations studied to date act by reducing the ATP sensitivity of the KATP channel. In general,mutations that cause PNDM impair ATP binding and/or transduction of ATP binding into pore closure,whereas mutations that cause DEND syndrome act indirectly, by stabilizing the open state of the channel which thereby decreases ATP block.We now report a mutation, R50P, in the putative ATP-binding site of Kir6.2 that severely impairs ATP sensitivity and results in DEND syndrome.