HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) All Versions of this Article: EJE-08-0203v1 159/1/27    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Christesen, H. Articles by Gloyn, A. Search for Related Content PubMed PubMed Citation Articles by Christesen, H. Articles by Gloyn, A.

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

H Christesen, H.C.Andersen Children's Hospital, Odense University hospital, odense, 5000, Denmark
N Tribble, Diabetes Research Laboratories, Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom
A Molven, The Gade Institute, University of Bergen, Bergen, Norway
J Siddiqui, Diabetes Research Laboratories, Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom
T Sandal, The Gade Institute, University of Bergen, Bergen, Norway
K Brusgaard, Dept. of Clinical Genetics, BFG, Odense University Hospital, Odense, Denmark
S Ellard, Institute of Biomedical & Clinical Science, Peninsula Medical School, Exeter, United Kingdom
P Njoelstad, Dept. of Clinical Medicine, University of Bergen, Bergen, Norway
J Alm, Dept. of Paediatrics, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
B Jacobsen, H.C.Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
K Hussain, Great Ormond Street Hospital, Institute of Child Health, University College London, London, United Kingdom
A Gloyn, Diabetes Research Laboratories, Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom

Correspondence: Henrik Christesen, Email: henrik.christesen{at}ouh.regionsyddanmark.dk

Abstract

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, 26; UK, 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, A456V) were identified, of which S64Y was novel. Two of the mutations arose de novo, three were dominantly inherited. All five patients were medically responsive. In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to 1.2% (2/167, 95% confidence interval 0-2.8%) of all CHI patients. In the 3 centre combined cohort of 72 medically responsive children without KATP-channel mutations, the prevalence estimate was 6.9% (5/72, 95% C.I. 1.1-12.8%). All GCK activating 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 protein, respectively), extrapolating to a relative activity index of ~22 compared to wild type.

Conclusion: In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive patients 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:

				C. Bellanne-Chantelot, C. Saint-Martin, M.-J. Ribeiro, C. Vaury, V. Verkarre, J.-B. Arnoux, V. Valayannopoulos, S. Gobrecht, C. Sempoux, J. Rahier, et al. ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism J. Med. Genet., August 3, 2010; (2010) jmg.2009.075416v1. [Abstract] [Full Text]

				F. Barbetti, N. Cobo-Vuilleumier, C. Dionisi-Vici, S. Toni, P. Ciampalini, O. Massa, P. Rodriguez-Bada, C. Colombo, L. Lenzi, M. A. Garcia-Gimeno, et al. Opposite Clinical Phenotypes of Glucokinase Disease: Description of a Novel Activating Mutation and Contiguous Inactivating Mutations in Human Glucokinase (GCK) Gene Mol. Endocrinol., December 1, 2009; 23(12): 1983 - 1989. [Abstract] [Full Text] [PDF]

				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]