title: Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies.
abstract: OBJECTIVE
  Congenital hyperinsulinism (CHI) is a cause of persistent and severe hypoglycaemia in infancy. Mutations in the genes ABCC8 and KCNJ11 encoding SUR1 and Kir6.2, respectively, are the commonest cause of CHI. We investigated whether the possession of two DNA variants leading to coding changes in a single allele of ABCC8 can affect the potential mechanism of disease pathogenesis.
  
  
  METHODS
  We studied two patients with complex mutations in the ABCC8 gene with CHI and used in vitro studies to explore the potential disease mechanism and the contribution of the various mutant allelles.
  
  
  RESULTS
  The first case had diffuse disease and was homozygous for the mutations D1193V and R1436Q in SUR1. Channel complexes containing the D1193V mutant were delivered to the plasma membrane and were functional and those containing R1436Q were also present at the plasma membrane but were nonfunctional. Combining the two mutations (SUR1D1193V/R1436Q) led to intracellular retention of the channel complex. In a second family, the patient had histologically focal disease and was heterozygous for two mutations from his father (G228D and D1471N) and one from his mother (V1572I). SUR1 G228D and D1471N singly or in combination led to intracellular retention of the channel complex and loss of function. By contrast, V1572I is trafficked appropriately and is functional, consistent with a mechanism of reduction to hemizygosity of paternal ABCC8 in focal disease. V1572I is likely to be a benign DNA variant.
  
  
  CONCLUSIONS
  In one patient the combination of two coding variants led to intracellular retention of channel complex. In a second patient, functional studies allowed us to unravel the DNA variants likely to be causing the abrogation of ATP-sensitive K(+) channel function.
authors.affiliation: BHF Laboratories and Department of Medicine, University College London, London, UK.
authors.forename: Morris
authors.initials: M
authors.lastname: Muzyamba
authors.forename: Tabasum
authors.initials: T
authors.lastname: Farzaneh
authors.forename: Phillip
authors.initials: P
authors.lastname: Behe
authors.forename: Alison
authors.initials: A
authors.lastname: Thomas
authors.forename: Henrik B T
authors.initials: HB
authors.lastname: Christesen
authors.forename: Klaus
authors.initials: K
authors.lastname: Brusgaard
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D016022:Case-Control Studies; D044903:Congenital Hyperinsulinism / Q000235:genetics*; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics* / Q000378:metabolism; D013194:Staining and Labeling; D064233:Sulfonylurea Receptors; D014162:Transfection / Q000379:methods; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human; C577508:Abcc8 protein, mouse