title: Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy.
abstract: OBJECTIVE
  Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a disorder of glucose metabolism that is characterized by dysregulated secretion of insulin from pancreatic beta-cells. This disease has been reported to be associated with mutations of the sulfonylurea receptor SUR1 (ABCC8) or the inward-rectifying potassium channel Kir6.2 (KCNJ11), which are two subunits of the pancreatic beta-cell ATP-sensitive potassium channel.
  
  
  METHODS
  In 14 Japanese PHHI patients, all exons of SUR1 and Kir6.2 genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Four patients responded to diazoxide, and nine patients underwent a subtotal pancreatectomy. Histologically, seven patients were diagnosed to have a focal form and two a diffuse form of the disease.
  
  
  RESULTS
  We found nine novel mutations in the SUR1 gene and two in the Kir6.2 gene. In the SUR1 gene mutations, three were nonsense mutations (Y512X, Y1354X and G1469X), one was a one-base deletion in exon 7, and two were missense mutations in the nucleotide-binding domain 2 (K1385Q, R1487K). The other three mutations occurred in introns 14, 29 and 36, which might cause aberrant splicing of RNA. Two siblings in one family were heterozygotes for a missense mutation, K1385Q, which was maternally inherited. In Kir6.2 gene screening, one patient was found to be a compound heterozygote of a missense mutation (R34H) and a one-base deletion (C344fs/ter).
  
  
  CONCLUSIONS
  The novel mutations reported here could be pathological candidates for PHHI in Japan. They also reveal that SUR1 and Kir6.2 mutations in the Japanese population exhibit heterogeneity and that they occurred at a frequency similar to other genetic populations.
authors.affiliation: Department of Laboratory Medicine, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. kokubo@cis.fukuoka-u.ac.jp
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ohkubo
authors.forename: Mariko
authors.initials: M
authors.lastname: Nagashima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Naito
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Taguchi
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Suita
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Hideshi
authors.initials: H
authors.lastname: Fujinaga
authors.forename: Kumi
authors.initials: K
authors.lastname: Tsumura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Junko
authors.initials: J
authors.lastname: Ono
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D044466:Asian People; D002462:Cell Membrane / Q000378:metabolism; D044903:Congenital Hyperinsulinism / Q000235:genetics* / Q000378:metabolism; D005819:Genetic Markers; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000201:enzymology*; D007564:Japan; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D005819:Genetic Markers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate