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

HC Andersen Children's Hospital, Odense University Hospital, DK-5000 Odense C, Denmark¹ Diabetes Research Laboratories, Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK² The Gade Institute,, University of Bergen, N-5021 Bergen, Norway³ Department of Pathology,, Haukeland University Hospital, N-5021 Bergen, Norway⁴ Department of Clinical Medicine,, University of Bergen, N-5021 Bergen, Norway⁵ Department of Clinical Genetics,, Odense University Hospital, DK-5000 Odense C, Denmark⁶ Peninsula Medical School,, Institute of Biomedical and Clinical Science, Exeter EX2 5DW, UK⁷ Department of Pediatrics,, Haukeland University Hospital, N-5021 Bergen, Norway⁸ Department of Paediatrics Karolinska Institute,, Karolinska University Hospital, S-171 76 Stockholm, Sweden and ⁹ Great Ormond Street Hospital,, University College London, London WC1N 3JH, UK

(Correspondence should be addressed to A L Gloyn at Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK; Email: anna.gloyn{at}drl.ox.ac.uk)

^* H B T Christesen and N D Tribble contributed equally to this work

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 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 (7%) suggests that screening for activating GCK mutations is warranted in those patients.

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