Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function
| Autor: | Victor Bancila, Yukio Tanizawa, Eric Marthinet, Yoshimoto Oka, Jean-Michel Marie Maurice Dubuis, Valerie M. Schwitzgebel, Jacques Philippe, Alain Bloc, Bernhard Wehrle-Haller |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Potassium Channels
Patch-Clamp Techniques Endocrinology Diabetes and Metabolism medicine.medical_treatment Receptors Drug Adenosine Triphosphate/metabolism Clinical Biochemistry Fluorescent Antibody Technique medicine.disease_cause Sulfonylurea Receptors Biochemistry 0302 clinical medicine Endocrinology Adenosine Triphosphate ddc:616 0303 health sciences ddc:618 Microscopy Confocal Homozygote Hyperinsulinism/congenital/genetics Kir6.2 Immunohistochemistry Potassium channel 3. Good health Protein Transport endocrine system medicine.medical_specialty Receptors Drug/genetics/metabolism Molecular Sequence Data Mutation Missense 030209 endocrinology & metabolism Context (language use) Hypoglycemia Transfection Cell Line 03 medical and health sciences Internal medicine Hyperinsulinism medicine Humans Amino Acid Sequence Potassium Channels Inwardly Rectifying Hyperinsulinemic hypoglycemia ddc:612 030304 developmental biology Staining and Labeling business.industry Insulin Potassium Channels/genetics/metabolism Biochemistry (medical) Infant Newborn medicine.disease Congenital hyperinsulinism Sulfonylurea receptor ATP-Binding Cassette Transporters/genetics/metabolism ATP-Binding Cassette Transporters Potassium Channels Inwardly Rectifying/genetics/metabolism/physiology business |
| Zdroj: | Journal of Clinical Endocrinology and Metabolism, Vol. 90, No 9 (2005) pp. 5401-6 |
| ISSN: | 0021-972X |
| Popis: | 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 beta-cells. A loss of function of K(ATP) channels causes depolarization of beta-cells and congenital hyperinsulinism (CHI), a disease presenting with severe hypoglycemia in the newborn period.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.We combined immunohistochemistry, advanced life fluorescence imaging, and electrophysiology in HEK293T cells transiently transfected with mutant Kir6.2.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.We assessed patch-clamp recordings and confocal microscopy in HEK293T cells.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.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. |
| Databáze: | OpenAIRE |
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