title: Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations.
abstract: Congenital hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.
authors.affiliation: Medical Genetics, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy. faletra@burlo.trieste.it
authors.forename: Flavio
authors.initials: F
authors.lastname: Faletra
authors.forename: Kara
authors.initials: K
authors.lastname: Snider
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
authors.forename: Irene
authors.initials: I
authors.lastname: Bruno
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Athanasakis
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ventura
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000188:drug therapy / Q000235:genetics*; D003981:Diazoxide / Q000627:therapeutic use; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D003981:Diazoxide