Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia
- 1 November 2009
- journal article
- review article
- Published by Hindawi Limited in Human Mutation
- Vol. 30 (11), 1512-1526
- https://doi.org/10.1002/humu.21110
Abstract
Glucokinase is a key regulatory enzyme in the pancreatic beta‐cell. It plays a crucial role in the regulation of insulin secretion and has been termed the glucose sensor in pancreatic beta‐cells. Given its central role in the regulation of insulin release it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyper‐ and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity‐onset diabetes of the young (MODY) subtype glucokinase (GCK), characterized by mild fasting hyperglycemia, which is present at birth but often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus (PNDM). A growing number of heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 620 mutations in the GCK gene have been described in a total of 1,441 families. There are no common mutations, and the mutations are distributed throughout the gene. The majority of activating mutations cluster in a discrete region of the protein termed the allosteric activator site. The identification of a GCK mutation in patients with both hyper‐ and hypoglycemia has implications for the clinical course and clinical management of their disorder. Hum Mutat 30: 1–15, 2009.Keywords
This publication has 172 references indexed in Scilit:
- Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live birthsDiabetologia, 2009
- Variants in MTNR1B influence fasting glucose levelsNature Genetics, 2008
- Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutationsJCI Insight, 2008
- Gene duplications resulting in over expression of glucokinase are not a common cause of hypoglycaemia of infancy in humansMolecular Genetics and Metabolism, 2008
- Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the youngDiabetologia, 2008
- Insulin gene mutations as a cause of permanent neonatal diabetesProceedings of the National Academy of Sciences of the United States of America, 2007
- Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A GenePLoS Medicine, 2007
- Glucokinase and IRS-2 are required for compensatory cell hyperplasia in response to high-fat diet-induced insulin resistanceJCI Insight, 2007
- A Common Haplotype of the Glucokinase Gene Alters Fasting Glucose and Birth Weight: Association in Six Studies and Population-Genetics AnalysesAmerican Journal of Human Genetics, 2006
- Dual Roles for Glucokinase in Glucose Homeostasis as Determined by Liver and Pancreatic β Cell-specific Gene Knock-outs Using Cre RecombinaseJournal of Biological Chemistry, 1999