title: A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.
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.
authors.affiliation: Transplantation Laboratory, Haartman Institute,and University of Helsinki, Finland. timo.otonkoski@helsinki.fi
authors.forename: T
authors.initials: T
authors.lastname: Otonkoski
authors.forename: C
authors.initials: C
authors.lastname: Ammälä
authors.forename: H
authors.initials: H
authors.lastname: Huopio
authors.forename: G J
authors.initials: GJ
authors.lastname: Cote
authors.forename: J
authors.initials: J
authors.lastname: Chapman
authors.forename: K
authors.initials: K
authors.lastname: Cosgrove
authors.forename: R
authors.initials: R
authors.lastname: Ashfield
authors.forename: E
authors.initials: E
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Komulainen
authors.forename: F M
authors.initials: FM
authors.lastname: Ashcroft
authors.forename: M J
authors.initials: MJ
authors.lastname: Dunne
authors.forename: J
authors.initials: J
authors.lastname: Kere
authors.forename: P M
authors.initials: PM
authors.lastname: Thomas
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D004594:Electrophysiology; D005260:Female; D005387:Finland; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications* / Q000235:genetics*; D007003:Hypoglycemia / Q000209:etiology* / Q000235:genetics*; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000235:genetics*; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D014982:Xenopus laevis
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate