title: Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization.
abstract: BACKGROUND
  Mutations in the GCK gene lead to different forms of glucokinase (GCK)-disease, activating mutations cause hyperinsulinaemic hypoglycaemia while inactivating mutations cause monogenic diabetes. Hyperinsulinism (HI) is a heterogeneous condition with a significant genetic component. The major causes are channelopathies, the other forms are rare and being caused by mutations in genes such as GCK.
  
  
  OBJECTIVE
  To describe the clinical and genetic presentation of four families with activating GCK mutations, and to explore the pathogenicity of the novel mutation identified through functional studies.
  
  
  RESULTS
  Four cases of HI with mutations in GCK were identified. These include one novel mutation (p.Trp99Cys). Functional analysis of the purified mutant fusion protein glutathione-S-transferase (GST)-GCK-p.Trp99Cys demonstrated that p.Trp99Cys is an activating mutation as it induces a higher affinity for glucose and increases the relative activity index more than 11 times. Moreover, the thermal stability of the mutant protein was similar to that of its wild type. All patients were responsive to diazoxide treatment. One of the mutations arose de novo, and two were dominantly inherited, although only one of them from an HI affected parent. The age of presentation in our cases varied widely from the neonatal period to adulthood.
  
  
  CONCLUSIONS
  The clinical phenotype of the GCK activating mutation carriers was heterogeneous, the severity of symptoms and age at presentation varied markedly between affected individuals, even within the same family. The novel activating GCK mutation (p.Trp99Cys) has a strong activating effect in vitro although it has been identified in one case of a milder and late-onset form of HI.
authors.affiliation: Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, UPV-EHU, CIBERDEM, CIBERER, Cruces University Hospital, Barakaldo, Spain.
authors.forename: Rosa
authors.identifier: http://orcid.org/0000-0003-3800-531X
authors.initials: R
authors.lastname: Martínez
authors.affiliation: Department of Biochemistry and Molecular Biology III, Faculty of Medicine, CIBERDEM and Hospital Clínico San Carlos Health Research Institute, Complutense University of Madrid, Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Gutierrez-Nogués
authors.affiliation: Pediatric Endocrinology Section, BioCruces Health Research Institute, UPV/EHU, Basurto University Hospital, Bilbao, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Fernández-Ramos
authors.affiliation: Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, UPV-EHU, CIBERDEM, CIBERER, Cruces University Hospital, Barakaldo, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Velayos
authors.affiliation: Pediatric Endocrinology Section, BioCruces Health Research Institute, UPV/EHU, Cruces University Hospital, CIBERDEM, CIBERER, Barakaldo, Bizkaia, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Vela
authors.affiliation: Department of Biochemistry and Molecular Biology III, Faculty of Medicine, CIBERDEM and Hospital Clínico San Carlos Health Research Institute, Complutense University of Madrid, Madrid, Spain.
authors.forename: María-Ángeles
authors.initials: MÁ
authors.lastname: Navas
authors.affiliation: Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, UPV-EHU, CIBERDEM, CIBERER, Cruces University Hospital, Barakaldo, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003981:Diazoxide / Q000627:therapeutic use; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D055550:Protein Stability; D055815:Young Adult
chemical_list: D005941:Glucokinase; D003981:Diazoxide