A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland

• Published in: Diabetes (New York, N.Y.) Vol. 48; no. 2; pp. 408 - 415
• Main Authors: OTONKOSKI, T, ÄMMÄLÄ, C, DUNNE, M. J, KERE, J, THOMAS, P. M, HUOPIO, H, COTE, G. J, CHAPMAN, J, COSGROVE, K, ASHFIELD, R, HUANG, E, KOMULAINEN, J, ASHCROFT, F. M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.1999
• Subjects: Adenosine Triphosphate - physiology; Animals; ATP-Binding Cassette Transporters; Biological and medical sciences; Diabetes; Disease; Electrophysiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Finland; Gene mutation; Gene mutations; Genes; Haplotypes; Haplotypes - genetics; Humans; Hyperinsulinism - complications; Hyperinsulinism - genetics; Hypoglycemia; Hypoglycemia - etiology; Hypoglycemia - genetics; Incidence; Infant; Infant, Newborn; Insulin; Islets of Langerhans - metabolism; Leukocytes; Male; Medical sciences; Mutation; Mutation - genetics; Pancreatic beta cells; Patients; Pediatrics; Physiological aspects; Point Mutation - genetics; Polymerase chain reaction; Potassium; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels - physiology; Potassium Channels, Inwardly Rectifying; Receptors, Drug - genetics; Recombinant Proteins; Sulfonylurea Receptors; Tumors. Hypoglycemia; Xenopus laevis; Europe; Finland; Northern Europe; Endocrinopathy; Human; Hyperinsulinemia; Langerhans islet; Ionic channel; Hypoglycemia; Genetic disease; Sulfonylureas; Mutation; Molecular biology; Child; Haplotype; Potassium; Endocrine pancreas; Biological receptor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.48.2.408

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. T Otonkoski , C Ammälä , H Huopio , G J Cote , J Chapman , K Cosgrove , R Ashfield , E Huang , J Komulainen , F M Ashcroft , M J Dunne , J Kere and P M Thomas Transplantation Laboratory, Haartman Institute,and University of Helsinki, Finland. timo.otonkoski@helsinki.fi Abstract Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.