Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation.

<jats:sec><jats:title>Objective</jats:title><jats:p>Activating glucokinase (<jats:italic>GCK</jats:italic>) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of <jats:italic>GCK</jats:italic> mutations is not known.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>From a pooled cohort of 201 non-syndromic children with CHI from three European referral centres (Denmark, <jats:italic>n</jats:italic>=141; Norway, <jats:italic>n</jats:italic>=26; UK, <jats:italic>n</jats:italic>=34), 108 children had no K<jats:sub>ATP</jats:sub>-channel (<jats:italic>ABCC8</jats:italic>/<jats:italic>KCNJ11</jats:italic>) gene abnormalities and were screened for <jats:italic>GCK</jats:italic> mutations. Novel <jats:italic>GCK</jats:italic> mutations were kinetically characterised.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In five patients, four heterozygous <jats:italic>GCK</jats:italic> mutations (S64Y, T65I, W99R and A456V) were identified, out of which S64Y was novel. Two of the mutations arose <jats:italic>de novo</jats:italic>, 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<jats:sub>ATP</jats:sub>-channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1–12.8%). All activating <jats:italic>GCK</jats:italic> mutations mapped to the allosteric activator site. The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S<jats:sub>0.5</jats:sub> 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 ∼22 compared with the wild type.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>In the largest study performed to date on <jats:italic>GCK</jats:italic> in children with CHI, <jats:italic>GCK</jats:italic> mutations were found only in medically responsive children who were negative for <jats:italic>ABCC8</jats:italic> and <jats:italic>KCNJ11</jats:italic> mutations. The estimated prevalence (∼7%) suggests that screening for activating <jats:italic>GCK</jats:italic> mutations is warranted in those patients.</jats:p></jats:sec>