title: Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: an unusual clinical picture.
abstract: BACKGROUND
  Inheritance of two pathogenic ABCC8 alleles typically causes severe congenital hyperinsulinism. We describe a girl and her father, both homozygous for the same ABCC8 mutation, who presented with unusual phenotypes.
  
  
  METHODS
  Single nucleotide polymorphism microarray and Sanger sequencing were performed. Western blot, rubidium efflux, and patch clamp recordings interrogated the expression and activity of the mutant protein.
  
  
  RESULTS
  A 16-month-old girl of consanguineous descent manifested hypoglycemia. She had dysregulation of insulin secretion, with postprandial hyperglycemia followed by hypoglycemia. Microarray revealed homozygosity for the regions encompassing KCNJ11 and ABCC8. Her father had developed diabetes at 28 years of age. Sequencing of ABCC8 identified a homozygous missense mutation, p.R1419H, in both individuals. Functional studies showed absence of working KATP channels.
  
  
  CONCLUSIONS
  This is the first description of a homozygous p.R1419H mutation. Our findings highlight that homozygous loss-of-function mutations of ABCC8 do not necessarily translate into early-onset severe hyperinsulinemia.
authors.forename: Shira
authors.initials: S
authors.lastname: Harel
authors.forename: Ana S A
authors.initials: AS
authors.lastname: Cohen
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Kamilla
authors.initials: K
authors.lastname: Schlade-Bartusiak
authors.forename: Millan
authors.initials: M
authors.lastname: Patel
authors.forename: Jaques
authors.initials: J
authors.lastname: Courtade
authors.forename: Jenny B W
authors.initials: JB
authors.lastname: Li
authors.forename: Clara
authors.initials: C
authors.lastname: Van Karnebeek
authors.forename: Harley
authors.initials: H
authors.lastname: Kurata
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Chanoine
authors.forename: William T
authors.initials: WT
authors.lastname: Gibson
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D002478:Cells, Cultured; D003241:Consanguinity; D005190:Family; D005260:Female; D006639:Histidine / Q000235:genetics; D006720:Homozygote; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007003:Hypoglycemia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D064233:Sulfonylurea Receptors / Q000235:genetics*
chemical_list: C577507:ABCC8 protein, human; D064233:Sulfonylurea Receptors; D006639:Histidine; D001120:Arginine