A conserved tryptophan at the membrane–water interface acts as a gatekeeper for Kir6.2/SUR1 channels and causes neonatal diabetes when mutated

摘要

Non-technical summaryNeonatal diabetes is a rare genetic form of diabetes that develops within the first 6 months of life. It is often caused by genetic defects (mutations) in a specialised membrane protein known as the KATP channel. This protein acts as a tiny pore in the membrane of the insulin-secreting cells in the pancreas and its opening and closing is regulated by blood glucose levels. Low blood glucose holds the pore open and prevents insulin secretion whereas high blood sugar leads to channel closure and insulin secretion. We identified a novel mutation (Kir6.2-W68R) that prevents channel closure and insulin secretion, and so results in neonatal diabetes. Detailed molecular studies showed that channel opening and closing is disrupted, suggesting Kir6.2-W68 may act as a channel ‘gatekeeper’. Our results also indicated that the mutant channel could be shut by sulphonylurea drugs, which enabled the patient to transfer from insulin injections to tablet therapy.