Functional Characterization of a Novel Heterozygous Mutation in the Glucokinase Gene That Causes MODY2 in Chinese Pedigrees

BackgroundGlucokinase (GCK) plays a central role in glucose regulation. The heterozygous mutations of GCK can cause a monogenic form of diabetes, maturity-onset diabetes of the young (MODY) directly. In our study, we aimed to explore the mechanism of the novel mutation GCK p.Ala259Thr leading to glucokinase deficiency and hyperglycemia.MethodsThirty early-onset diabetes pedigrees were referred to whole exome sequencing for novel mutations identification. Purified wild-type and mutant GCK proteins were obtained from E.coli systems and then subjected to the kinetic and thermal stability analysis to test the effects on GCK activity.ResultsOne novel missense mutation GCK p.Ala259Thr was identified and co-segregated with diabetes in a Chinese MODY2 pedigree. The kinetic analysis showed that this mutation result in a decreased affinity and catalytic capability for glucose. The thermal stability analysis also indicated that the mutant protein presented dramatically decreased activity at the same temperature.ConclusionOur study firstly identified a novel MODY2 mutation p.Ala259Thr in Chinese diabetes pedigrees. The kinetic and thermal stability analysis confirmed that this mutation caused hyperglycemia through severely damaging the enzyme activities and protein stability.

Molecular changes in the Glucokinase gene (GCK) associated with the diagnosis of Maturity Onset Diabetes of the Young (MODY) in pregnant women and newborns

Background: Diabetes Mellitus is the most common metabolic alteration in gestation. Monogenic diabetes or Maturity-Onset Diabetes of the Young (MODY) consists in a subtype caused by primary defect in insulin secretion determined by dominant autosomal inheritance. Objectives: To analyze molecular changes of the Glucokinase gene (GCK) in pregnant women with hyperglycemia during gestation and in their neonates. Case study and Methods: We collected 201 blood samples, 128 from pregnant patients diagnosed with hyperglycemia and 73 from umbilical cord blood from neonates of the respective patients. We performed DNA extraction and polymerase chain reaction (PCR) to identify molecular changes in the GCK gene. Results: In a total of 201 samples (128 from mothers and 73 from neonates), we found changes in 21 (10.6%), 12 maternal samples (6.0%) and 9 neonatal samples (4.5%). DNA sequencing identified two polymorphisms and one deleterious MODY GCK-diagnostic mutation. Conclusions: The prevalence of molecular changes of the Glucokinase gene (GCK) and the deleterious MODY GCK-diagnostic mutation were, respectively, 9.3% and 0.7% in women with hyperglycemia during gestation and 12.5% and 1.3% in their neonates. The deleterious MODY GCK mutation identified is associated reduction in GCK activity and hyperglycemia. In the others molecular changes identified despite not having clinical significance, it was not possible to exclude phenotypic change. Therefore, these changes may interfere with the management and clinical outcome of the patients.

Raised blood glucose due to heterozygous glucokinase gene mutation (GCK-MODY) diagnosed for the first time in pregnancy: The dilemmas and successful management – Case report and review of literature

Glucokinase mutation (GCK-MODY) is frequently misdiagnosed as either type I or type II diabetes mellitus, especially if presented for the first time during pregnancy. Generally GCK-MODY affects 1–2% of individuals with a diagnosis of diabetes. The defect in the glucose sensing mechanism in GCK-MODY results in a higher set point for maintenance of glucose homeostasis. Treatment is not recommended outside the pregnancy; however, in pregnancy, fetal abdominal circumference helps to decide about the likelihood of the fetus having inherited the condition and therefore whether insulin is required in pregnancy. We present a case in which GCK-MODY was diagnosed for the first time after pregnancy; the subsequent pregnancy was uneventful. Genetic testing is mandatory to establish the diagnosis. Here the implications of MODY and its subtypes, along with the pattern of inheritance and management aspects are discussed.

MODY2 diagnostic issues in adults

Approximately 90% of all cases of diabetes mellitus in adults involve type 2 diabetes, while the prevalence of maturity-onset diabetes of the young (MODY) remains undetermined leading to inappropriate treatment regimens. One of the most common monogenic forms of diabetes is a disease caused by a mutation in the glucokinase gene, MODY2. Knowledge of the clinical features of the disease allows the selection of patients with a high risk of mutation in the glucokinase gene and verification of diagnosis for molecular genetic research. This paper reflects the clinical features of MODY2 and the difficulties of diagnosis in adults. Furthermore, it presents a clinical case of a patient with MODY2 demonstrating all the features of this type of diabetes. A family member with a mutation in the gene allows to predict the nature of carbohydrate metabolism disorders in first degree relatives. A targeted study of only one part of the glucokinase gene in molecular genetic research is sufficient to confirm the diagnosis in relatives.