title: An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes.
abstract: Mutations in the pancreatic ATP-sensitive K(+) channel (K(ATP) channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the K(ATP) channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of K(ATP) channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg . kg(-1) . day(-1)) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Ricard
authors.initials: R
authors.lastname: Masia
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Koster
authors.forename: Stefano
authors.initials: S
authors.lastname: Tumini
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiarelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Colombo
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Barbetti
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000483:Alleles; D001665:Binding Sites / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital / Q000188:drug therapy / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D064233:Sulfonylurea Receptors; D013577:Syndrome; D014044:Tolbutamide / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel