Abstract and Introduction
Closure of ATP-sensitive K+ channels (KATP channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic β-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in ~47% of patients diagnosed with permanent diabetes at <6 months of age. There is a striking genotype-phenotype relationship with specific Kir6.2 mutations being associated with transient neonatal diabetes, permanent neonatal diabetes alone, and a novel syndrome characterized by developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. All mutations appear to cause neonatal diabetes by reducing KATP channel ATP sensitivity and increasing the KATP current, which inhibits β-cell electrical activity and insulin secretion. The severity of the clinical symptoms is reflected in the ATP sensitivity of heterozygous channels in vitro with wild type > transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated KATP channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the KATP channel.
Neonatal diabetes diagnosed within the first 3 months of life is usually a single gene disorder associated with altered β-cell number or function. Transient neonatal diabetes resolves by a median of 12 weeks and is generally associated with an abnormality of the imprinted region 6q24. In contrast, permanent neonatal diabetes requires insulin treatment for life, and until recently the genetic etiology was largely unknown. Thus, the discovery that heterozygous gain-of-function mutations in KCNJ11 cause permanent neonatal diabetes in almost half of cases is an important advance.KCNJ11 encodes Kir6.2, the pore-forming subunit of the ATP-sensitive K+ channel (KATP channel). This article summarizes recent genetic, clinical, and functional work on Kir6.2 mutations that cause neonatal diabetes.
Diabetes. 2005;54(9):2503-2513. © 2005 American Diabetes Association, Inc.
Cite this: Activating Mutations in Kir6.2 and Neonatal Diabetes - Medscape - Sep 01, 2005.