title: Mutation spectra of ABCC8 gene in Spanish patients with Hyperinsulinism of Infancy (HI).
abstract: Hyperinsulinism of Infancy (HI) is a clinical disorder characterized by deregulation of insulin secretion that leads to profound hypoglycemia. Mutations in genes encoding the ATP-regulated potassium channels of the pancreatic beta-cell, namely ABCC8 (SUR1) and KCNJ11 (Kir6.2), are the major genetic known cause of the disease. To elucidate the genetic etiology of HI in the uncharacterized Spanish population, we conducted extensive sequencing analysis of the ABCC8 (83.5Kb) and KCNJ11 (1.7Kb) genes in 34 Spanish HI patients. Mutations in ABCC8 were detected for both alleles in 13 patients, while ten patients carried only one mutation in one of the ABCC8 alleles. We have detected 22 novel and seven previously described mutations in ABCC8, approximately 60% of them lead to a premature termination signal, which would result in truncated SUR1 proteins. No mutations were found in the KCNJ11 gene. In addition, we report for the first time a 3914bp macrodeletion associated with the HI disorder. The potential pathogenicity of several additional variants is discussed. The spatial pattern of three pathological mutations suggests possible geographical founder effects. This work reveals for first time the involvement of KATP channels in the pathogenesis of an important proportion (approximately 68%) of Spanish HI patients. The spectrum of mutations in Spanish HI patients provides an important tool for diagnosis and prognosis of HI patients in the Spanish population, as well as for genetic counseling of HI families.
authors.affiliation: Unidad de Medicina Molecular, Fundación Pública Galega de Medicina Xenómica, SERGAS, Hospital Clínico Universitario de Santiago, Galicia, Spain. ana.fernandez.marmiesse@sergas.es
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Marmiesse
authors.forename: Antonio
authors.initials: A
authors.lastname: Salas
authors.forename: Ana
authors.initials: A
authors.lastname: Vega
authors.forename: José Ramón
authors.initials: JR
authors.lastname: Fernández-Lorenzo
authors.forename: Jesús
authors.initials: J
authors.lastname: Barreiro
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D044903:Congenital Hyperinsulinism / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D006239:Haplotypes; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D013030:Spain; D064233:Sulfonylurea Receptors
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