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The G53D Mutation in Kir6.2 (KCNJ11) Is Associated with Neonatal Diabetes and Motor Dysfunction in Adulthood that Is Improved with Sulfonylurea Therapy

Department of Cell Biology and Physiology (J.C.K., C.G.N.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Pediatrics (F.C.), Interdisciplinary Research Center for Autoimmune Disease, A. Avogadro University of Eastern Piedmont, and Division of Child Neurology and Psychiatry (C.P.), Azienda Ospedaliera "Maggiore della Carita," 28100 Novara, Italy; Bambino Gesu Children’s Hospital (C.C., F.B.), Instituto di Ricovero e Cura a Carattere Scientifico, 00164 Rome, Italy; S. Raffaele Scientific Park Foundation (F.B.), 00128 Rome, Italy; and Department of Internal Medicine (F.B.), University of Tor Vergata, 00133 Rome, Italy

Address all correspondence and requests for reprints to: Joseph C. Koster, Ph.D., Washington University School of Medicine, Department of Cell Biology and Physiology, Box 8228, St. Louis, MO 63110. E-mail: jkoster{at}cellbiology.wustl.edu; or Fabrizio Barbetti, M.D., Ph.D., S. Raffaele Scientific Foundation, Room B303, Via di Castelromano, 100, 00128 Rome, Italy. E-mail: fabrizio.barbetti{at}spr-r.it.

Context: Mutations in the Kir6.2 subunit (KCNJ11) of the ATP-sensitive potassium channel (K_ATP) underlie neonatal diabetes mellitus. In severe cases, Kir6.2 mutations underlie developmental delay, epilepsy, and neonatal diabetes (DEND). All Kir6.2 mutations examined decrease the ATP inhibition of K_ATP, which is predicted to suppress electrical activity in neurons (peripheral and central), muscle, and pancreas. Inhibitory sulfonylureas (SUs) have been used successfully to treat diabetes in patients with activating Kir6.2 mutations. There are two reports of improved neurological features in SU-treated DEND patients but no report of such improvement in adulthood.

Objective: The objective of the study was to determine the molecular basis of intermediate DEND in a 27-yr-old patient with a KCNJ11 mutation (G53D) and the patient’s response to SU therapy.

Design: The G53D patient was transferred from insulin to gliclazide and then to glibenclamide over a 160-d period. Motor function was assessed throughout. Electrophysiology assessed the effect of the G53D mutation on K_ATP activity.

Results: The G53D patient demonstrated improved glycemic control and motor coordination with SU treatment, although glibenclamide was more effective than gliclazide. Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. G53D channels coexpressed with SUR1 (the pancreatic and neuronal isoform) exhibit high-affinity block by gliclazide but are insensitive to block when coexpressed with SUR2A (the skeletal muscle isoform). High-affinity block by glibenclamide is present in G53D channels coexpressed with either SUR1 or SUR2A.

Conclusion: The results demonstrate that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle K_ATP.

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				L. Aguilar-Bryan and J. Bryan Neonatal Diabetes Mellitus Endocr. Rev., May 1, 2008; 29(3): 265 - 291. [Abstract] [Full Text] [PDF]