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DOI: 10.2337/db05-1420
© 2006 by the American Diabetes Association
Functional Effects of Mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11), Causing Neonatal Diabetes, and Response to Sulfonylurea Therapy
1 University Laboratory of Physiology, Oxford University, Oxford, U.K
2 Innandet Hospital, Lillehammer, Norway
3 Section for Paediatrics, Department of Clinical Medicine, University of Bergen, Bergen, Norway
4 Department of Paediatrics, Haukeland University Hospital, Bergen, Norway
Address correspondence and reprint requests to Professor Frances Ashcroft, University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, U.K. E-mail: frances.ashcroft{at}physiol.ox.ac.uk
Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K+ channel (KATP channel), cause neonatal diabetes. To date, all mutations increase whole-cell KATP channel currents by reducing channel inhibition by MgATP. Here, we provide functional characterization of two mutations (F35L and F35V) at residue F35 of Kir6.2, which lies within the NH2-terminus. We further show that the F35V patient can be successfully transferred from insulin to sulfonylurea therapy. The patient has been off insulin for 24 months and shows improved metabolic control (mean HbA1c 7.58 before and 6.18% after sulfonylurea treatment; P < 0.007). Wild-type and mutant Kir6.2 were heterologously coexpressed with SUR1 in Xenopus oocytes. Whole-cell KATP channel currents through homomeric and heterozygous F35V and F35L channels were increased due to a reduced sensitivity to inhibition by MgATP. The mutation also increased the open probability (PO) of homomeric F35 mutant channels in the absence of ATP. These effects on PO and ATP sensitivity were abolished in the absence of SUR1. Our results suggest that mutations at F35 cause permanent neonatal diabetes by affecting KATP channel gating and thereby, indirectly, ATP inhibition. Heterozygous F35V channels were markedly inhibited by the sulfonylurea tolbutamide, accounting for the efficacy of sulfonylurea therapy in the patient.
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