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Eric Marthinet, Alain Bloc, Yoshimoto Oka, Yukio Tanizawa, Bernhard Wehrle-Haller, Victor Bancila, Jean-Michel Dubuis, Jacques Philippe, Valerie M. Schwitzgebel, Severe Congenital Hyperinsulinism Caused by a Mutation in the Kir6.2 Subunit of the Adenosine Triphosphate-Sensitive Potassium Channel Impairing Trafficking and Function, The Journal of Clinical Endocrinology & Metabolism, Volume 90, Issue 9, 1 September 2005, Pages 5401–5406, https://doi.org/10.1210/jc.2005-0202
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Abstract
Context: The ATP-sensitive potassium (KATP) channel, assembled from the inwardly rectifying potassium channel Kir6.2 and the sulfonylurea receptor 1, regulates insulin secretion in β-cells. A loss of function of KATP channels causes depolarization of β-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 Kir6.2H259R with sulfonylurea receptor 1 in HEK293T cells completely abolished KATP 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.
