title: Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy.
abstract: OBJECTIVE
  Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic ATP-sensitive K(+) channel are the most common cause of permanent neonatal diabetes. In contrast to KCNJ11, where only dominant heterozygous mutations have been identified, recessively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome 11p15.1, centromeric to the imprinted Beckwith-Wiedemann syndrome (BWS) locus at 11p15.5. We investigated a male with hemihypertrophy, a condition classically associated with neonatal hyperinsulinemia and hypoglycemia, who developed neonatal diabetes at age 5 weeks.
  
  
  METHODS
  The KCNJ11 and ABCC8 genes and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and his parents.
  
  
  RESULTS
  A paternally inherited activating mutation (N72S) in the ABCC8 gene was identified in the proband. The mutation was present at 70% in the patient's leukocytes and 50% in buccal cells. Microsatellite analysis demonstrated mosaic segmental paternal uniparental isodisomy (UPD) of 11pter-11p14 in the proband that encompassed the ABCC8 gene and the BWS locus.
  
  
  CONCLUSIONS
  We report a patient with neonatal diabetes, hemihypertrophy, and relatively high birth weight resulting from telomeric segmental paternal UPD of chromosome 11, which unmasks a recessively acting gain-of-function mutation in the ABCC8 gene and causes deregulation of imprinted genes at the BWS locus on 11p15.5.
authors.affiliation: Department of Endocrinology and Diabetes, Bristol Royal Hospital for Children and University of Bristol, Bristol, UK.
authors.forename: Julian P H
authors.initials: JP
authors.lastname: Shield
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Mackay
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.forename: Peter
authors.initials: P
authors.lastname: Proks
authors.forename: Christophe
authors.initials: C
authors.lastname: Girard
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology*; D007839:Functional Laterality; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats; D009030:Mosaicism; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D024182:Uniparental Disomy / Q000235:genetics*
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors