title: Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
abstract: Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
authors.affiliation: Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Sharona
authors.initials: S
authors.lastname: Tornovsky
authors.forename: Ana
authors.initials: A
authors.lastname: Crane
authors.forename: Karen E
authors.initials: KE
authors.lastname: Cosgrove
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.forename: Judith
authors.initials: J
authors.lastname: Lavie
authors.forename: Ma'ayan
authors.initials: M
authors.lastname: Heyman
authors.forename: Yaron
authors.initials: Y
authors.lastname: Nesher
authors.forename: Na'ama
authors.initials: N
authors.lastname: Kuchinski
authors.forename: Etti
authors.initials: E
authors.lastname: Ben-Shushan
authors.forename: Olga
authors.initials: O
authors.lastname: Shatz
authors.forename: Efrat
authors.initials: E
authors.lastname: Nahari
authors.forename: Tamara
authors.initials: T
authors.lastname: Potikha
authors.forename: David
authors.initials: D
authors.lastname: Zangen
authors.forename: Yardena
authors.initials: Y
authors.lastname: Tenenbaum-Rakover
authors.forename: Liat
authors.initials: L
authors.lastname: de Vries
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gracia
authors.forename: Heddy
authors.initials: H
authors.lastname: Landau
authors.forename: Alon
authors.initials: A
authors.lastname: Eliakim
authors.forename: Keith
authors.initials: K
authors.lastname: Lindley
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunne
authors.forename: Lydia
authors.initials: L
authors.lastname: Aguilar-Bryan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000225:Adenine; D002874:Chromosome Mapping; D015331:Cohort Studies; D004594:Electrophysiology; D018740:Genetic Heterogeneity; D006147:Guanine; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000503:physiopathology; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000503:physiopathology; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000225:Adenine; D006147:Guanine; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human