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Congenital hyperinsulinism-associated ABCC8 mutations that cause defective trafficking of ATP-sensitive potassium channels: identification and rescue

¹Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, OR 97239;
²Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; and
³Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.

Correspondence: shyngs{at}ohsu.edu

Objective:Congenital hyperinsulinism (CHI) is a disease characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive potassium (K_ATP) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11 respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Previous studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide. The purpose of this study is to identify additional mutations that cause channel biogenesis/trafficking defects and those that are amenable to rescue by pharmacological chaperones.

Resarch design and methods:Fifteen previously uncharacterized CHI-associated missense SUR1 mutations were examined for their biogenesis/trafficking defects and responses to pharmacological chaperones, using a combination of immunological and functional assays.

Results:Twelve of the fifteen mutations analyzed cause reduction in cell surface expression of K_ATP channels by more than 50%. Sulfonylureas rescued a subset of the trafficking mutants. By contrast, diazoxide failed to rescue any of the mutants. Strikingly, the mutations rescued by sulfonylureas are all located in the first transmembrane domain of SUR1 designated as TMD0. All TMD0 mutants rescued to the cell surface by the sulfonylurea tolbutamide could be subsequently activated by metabolic inhibition upon tolbutamide removal.

Conclusions:Our study identifies a group of CHI-causing SUR1 mutations for which the resulting K_ATP channel trafficking and expression defects may be corrected pharmacologically to restore channel function.

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