title: Three novel pathogenic mutations in KATP channel genes and somatic imprinting alterations of the 11p15 region in pancreatic tissue in patients with congenital hyperinsulinism.
abstract: OBJECTIVE
  This study was performed to investigate the molecular pathology underlying focal and diffuse congenital hyperinsulinism (CHI).
  
  
  METHODS
  The ABCC8 and KCNJ11 genes were analyzed in 3 patients with focal CHI and in 1 patient with diffuse CHI. Immunohistochemistry, real-time PCR, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and microsatellite marker analyses of the 11p15 region were performed on both normal tissues and adenomatous hyperplasia lesions.
  
  
  RESULTS
  The 3 patients with focal CHI harbored paternally inherited ABCC8 or KCNJ11 mutations. Compound heterozygous ABCC8 mutations were identified in the patient with diffuse CHI. In the 3 patients with focal CHI, homozygous ABCC8 or KCNJ11 mutations were identified within the lesions. MLPA and real-time PCR revealed the presence of two copies of 11p15. MS-MLPA and microsatellite analyses demonstrated abnormal imprinting patterns and focal loss of maternal 11p13-15 within the lesions. In contrast, parental heterozygosity was preserved in the normal tissue. In the patient with diffuse CHI, the two ABCC8 mutations were conserved, and imprinting patterns at 11p15 were normal.
  
  
  CONCLUSIONS
  The epigenetic alteration at the 11p15 region plays a central role in developing focal CHI by paternally derived mutations of the KATP channel and maternal allelic loss at this region. MS-MLPA and microsatellite analyses are useful to investigate the molecular etiology of CHI.
authors.affiliation: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Beom Hee
authors.initials: BH
authors.lastname: Lee
authors.forename: Jin
authors.initials: J
authors.lastname: Lee
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Minji
authors.initials: M
authors.lastname: Kang
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Jihun
authors.initials: J
authors.lastname: Kim
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.forename: Dae-Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Seong-Chul
authors.initials: SC
authors.lastname: Kim
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D044903:Congenital Hyperinsulinism / Q000378:metabolism / Q000473:pathology; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D010179:Pancreas / Q000473:pathology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D064233:Sulfonylurea Receptors / Q000235:genetics*; D000099161:Kcnj11 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human