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Severe Congenital Hyperinsulinism Caused by a Mutation in the Kir6.2 Subunit of the Adenosine Triphosphate-Sensitive Potassium Channel Impairing Trafficking and Function

Pediatric Endocrinology and Diabetology (E.M., J.-M.D., V.M.S.) and Diabetes Unit (E.M., J.P.), University Hospital of Geneva, and Departments of Neuroscience (A.B., V.B.) and Cellular Physiology and Metabolism (B.W.-H.), University of Geneva, CH-1211 Geneva, Switzerland; Biochemical Institute (A.B.), University of Lausanne, CH-1015 Lausanne, Switzerland; Department of Internal Medicine (Y.O.), Tohoku University Graduate School of Medicine Seiryo-machi, Sendai 980-8575, Japan; and Division of Molecular Analysis of Human Disorders (Y.T.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan

Address all correspondence and requests for reprints to: Valérie M. Schwitzgebel, Pediatric Endocrinology and Diabetology, Children’s Hospital, 6, rue Willy Donzé, CH-1211 Geneva, Switzerland. E-mail: valerie.schwitzgebel{at}hcuge.ch.

Context: The ATP-sensitive potassium (K_ATP) channel, assembled from the inwardly rectifying potassium channel Kir6.2 and the sulfonylurea receptor 1, regulates insulin secretion in ß-cells. A loss of function of K_ATP channels causes depolarization of ß-cells and congenital hyperinsulinism (CHI), a disease presenting with severe hypoglycemia in the newborn period.

Objective: Our objective was identification of a novel mutation in Kir6.2 in a patient with CHI and molecular and cell-biological analysis of the impact of this mutation.

Design and Setting: We combined immunohistochemistry, advanced life fluorescence imaging, and electrophysiology in HEK293T cells transiently transfected with mutant Kir6.2.

Patient and Intervention: The patient presented with macrosomia at birth and severe hyperinsulinemic hypoglycemia. Despite medical treatment, the newborn continued to suffer from severe hypoglycemic episodes, and at 4 months of age subtotal pancreatectomy was performed.

Main Outcome Measure: We assessed patch-clamp recordings and confocal microscopy in HEK293T cells.

Results: We have identified a homozygous missense mutation, H259R, in the Kir6.2 subunit of a patient with severe CHI. Coexpression of Kir6.2_H259R with sulfonylurea receptor 1 in HEK293T cells completely abolished K_ATP currents in electrophysiological recordings. Double immunofluorescence staining revealed that mutant Kir6.2 was partly retained in the endoplasmic reticulum (ER) causing decreased surface expression as observed with total internal reflection fluorescence. Mutation of an ER-retention signal partially rescued the trafficking defect without restoring whole-cell currents.

Conclusion: The H259R mutation of the Kir6.2 subunit results in a channel that is partially retained in the ER and nonfunctional upon arrival at the plasma membrane.

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