An ATP-Binding Mutation (G334D) in KCNJ11 Is Associated With a Sulfonylurea-Insensitive Form of Developmental Delay, Epilepsy, and Neonatal Diabetes

• DOI: 10.2337/db06-1275
• Publication Date: 2007-01-26T20:11:02Z
• Authors: Ricard Masia; Joseph C. Koster; Stefano Tumini; Francesco Chiarelli; Carlo Colombo; Colin G. Nichols; Fabrizio Barbetti
• Keywords: Sulfonylurea; Sulfonylurea receptor; Kir6.2

Mutations in the pancreatic ATP-sensitive K(+) channel (K(ATP) channel) cause permanent neonatal diabetes mellitus (PNDM) humans. All of K(ATP) mutations examined result decreased ATP inhibition, which turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, includes developmental delay and epilepsy, addition (developmental delay, [DEND]), due G334D mutation Kir6.2 subunit channel. The was wholly unresponsive sulfonylurea therapy (up 1.14 mg . kg(-1) day(-1)) remained dependent. Consistent putative role G334 as an ATP-binding residue, reconstituted homomeric mixed WT+G334D channels exhibit absent or reduced sensitivity but normal gating behavior absence ATP. In disagreement insensitivity affected patient, has no effect on inhibition excised patches. However, macroscopic rubidium-efflux assays intact cells, mutant do decreased, still present, response. results demonstrate that site can indeed DEND suggest possibility such patients may be secondary reflection presence rather than simple underlying molecular basis.