| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CLINICAL STUDIES |
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 KATP-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 KATP-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 (S0.5 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.
This article has been cited by other articles:
|
|
 |
|
  S. Sayed, D. R. Langdon, S. Odili, P. Chen, C. Buettger, A. B. Schiffman, M. Suchi, R. Taub, J. Grimsby, F. M. Matschinsky, et al. Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations Diabetes, June 1, 2009; 58(6): 1419 - 1427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C James, R R Kapoor, D Ismail, and K Hussain The genetic basis of congenital hyperinsulinism J. Med. Genet., May 1, 2009; 46(5): 289 - 299. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
