title: Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.
abstract: OBJECTIVE
  Activating glucokinase (GCK) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of GCK mutations is not known.
  
  
  METHODS
  From a pooled cohort of 201 non-syndromic children with CHI from three European referral centres (Denmark, n=141; Norway, n=26; UK, n=34), 108 children had no K(ATP)-channel (ABCC8/KCNJ11) gene abnormalities and were screened for GCK mutations. Novel GCK mutations were kinetically characterised.
  
  
  RESULTS
  In five patients, four heterozygous GCK mutations (S64Y, T65I, W99R and A456V) were identified, out of which S64Y was novel. Two of the mutations arose de novo, three were dominantly inherited. All the five patients were medically responsive. In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to be 1.2% (2/167, 95% confidence interval (CI) 0-2.8%) of all the CHI patients. In the three centre combined cohort of 72 medically responsive children without K(ATP)-channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1-12.8%). All activating GCK mutations mapped to the allosteric activator site. The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S(0.5) 1.49+/-0.08 and 7.39+/-0.05 mmol/l in mutant and wild-type proteins respectively), extrapolating to a relative activity index of approximately 22 compared with the wild type.
  
  
  CONCLUSIONS
  In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive children who were negative for ABCC8 and KCNJ11 mutations. The estimated prevalence (approximately 7%) suggests that screening for activating GCK mutations is warranted in those patients.
authors.affiliation: HC Andersen Children's Hospital, Odense University Hospital, DK-5000 Odense C, Denmark.
authors.forename: Henrik B T
authors.initials: HB
authors.lastname: Christesen
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Tribble
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Juveria
authors.initials: J
authors.lastname: Siddiqui
authors.forename: Tone
authors.initials: T
authors.lastname: Sandal
authors.forename: Klaus
authors.initials: K
authors.lastname: Brusgaard
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.forename: Jan
authors.initials: J
authors.lastname: Alm
authors.forename: Bendt
authors.initials: B
authors.lastname: Brock Jacobsen
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D015331:Cohort Studies; D044903:Congenital Hyperinsulinism / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D003718:Denmark / Q000453:epidemiology; D004789:Enzyme Activation / Q000187:drug effects; D005787:Gene Frequency; D005838:Genotype; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D009664:Norway / Q000453:epidemiology; D015995:Prevalence; D013379:Substrate Specificity; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D005941:Glucokinase; D005947:Glucose