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

作者：Christesen Henrik B T; Tribble Nicholas D; Molven Anders; Siddiqui Juveria; Sandal Tone; Brusgaard Klaus; Ellard Sian; Njolstad Pal R; Alm Jan; Jacobsen Bendt Brock; Hussain Khalid; Gloyn Anna L^*

来源：European Journal of Endocrinology, 2008, 159(1): 27-34.

DOI：10.1530/EJE-08-0203

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/KCNIJ11) gene abnormalities and were screened for GCK mutations. Novel GCK mutations were kinetically characterised.
Results: In five patients, four heterozygous GCK mutations (S64Y, T651, 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 1.1-12.89/0). 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 similar to 22 compared with the wild type.
Conclusion: 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 (similar to 7%) suggests that screening for activating GCK mutations is warranted in those patients.

• 出版日期2008-7