Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.
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.
Christesen
Henrik B T
HB
HC Andersen Children's Hospital, Odense University Hospital, DK-5000 Odense C, Denmark.
Tribble
Nicholas D
ND
Molven
Anders
A
Siddiqui
Juveria
J
Sandal
Tone
T
Brusgaard
Klaus
K
Ellard
Sian
S
Njølstad
Pål R
PR
Alm
Jan
J
Brock Jacobsen
Bendt
B
Hussain
Khalid
K
Gloyn
Anna L
AL
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
D005941:Glucokinase; D005947:Glucose