Research Article
Received: 14 December 2008; Accepted: 11 March 2009
10.1002/emmm.200900018 About DOI
Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism |
| Kenju Shimomura 1, Sarah E. Flanagan 2, Brittany Zadek 1, Mark Lethby 1, Lejla Zubcevic 1, Christophe A. J. Girard 1, Oliver Petz 3, Roope Mannikko 1, Ritika R. Kapoor 4, Khalid Hussain 4, Mars Skae 5, Peter Clayton 5, Andrew Hattersley 2, Sian Ellard 2, Frances M. Ashcroft 1 * |
| 1Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, UK 2Institute of Biomedical and Clinical Research, Peninsula Medical School, Exeter, UK 3St. Vincenz Hospital Coesfeld, Childrens Hospital, Germany 4London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust and The Institute of Child Health, University College London, UK 5Department of Endocrinology, Royal Manchester Children's Hospital, Central Manchester & Manchester Children's University Hospitals NHS Trust, UK |
| email: Frances M. Ashcroft (frances.ashcroft@dpag.ox.ac.uk) |
*Correspondence to Frances M. Ashcroft, Tel: +44 (0) 1865-285810; Fax: +44 (0) 1865-285813
| Keywords |
| channel gating hyperinsulinism KATP channel Kir6.2 neonatal diabetes |
| Abstract |
KATP channels regulate insulin secretion from pancreatic  -cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism of infancy and neonatal diabetes, respectively. We report two novel mutations in the gating loop of Kir6.2 which cause neonatal diabetes with developmental delay (T293N) and hyperinsulinism (T294M). These mutations increase (T293N) or decrease (T294M) whole-cell KATP currents, accounting for the different clinical phenotypes. The T293N mutation increases the intrinsic channel open probability (Po(0)), thereby indirectly decreasing channel inhibition by ATP and increasing whole-cell currents. T294M channels exhibit a dramatically reduced Po(0) in the homozygous but not in the pseudo-heterozygous state. Unlike wild-type channels, hetT294M channels were activated by MgADP in the absence but not in the presence of MgATP; however, they are activated by MgGDP in both the absence and presence of MgGTP. These mutations demonstrate the importance of the gating loop of Kir channels in regulating Po(0) and further suggest that Mg-nucleotide interaction with SUR1 may reduce ATP inhibition at Kir6.2. |
Received: 14 December 2008; Accepted: 11 March 2009
| Digital Object Identifier (DOI) |
10.1002/emmm.200900018 About DOI
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