title: Interaction between mutations in the slide helix of Kir6.2 associated with neonatal diabetes and neurological symptoms.
abstract: ATP-sensitive potassium (K(ATP)) channels regulate insulin secretion from pancreatic beta-cells. Gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause neonatal diabetes. We report two novel mutations on the same haplotype (cis), F60Y and V64L, in the slide helix of Kir6.2 in a patient with neonatal diabetes, developmental delay and epilepsy. Functional analysis revealed the F60Y mutation increases the intrinsic channel open probability (Po(0)), thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell K(ATP) currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same (but not a different) subunit. These data indicate that F60Y is the pathogenic mutation and reveal that interactions between slide helix residues can influence K(ATP) channel gating.
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Roope
authors.initials: R
authors.lastname: Männikkö
authors.forename: Craig
authors.initials: C
authors.lastname: Jefferies
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Andrew
authors.initials: A
authors.lastname: Hattersley
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D048909:Diabetes Complications / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D015640:Ion Channel Gating / Q000187:drug effects; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000150:complications* / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D054086:KATP Channels; D050505:Mutant Proteins; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D000099161:Kcnj11 Channel