ArticleDiabetologia2007
Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity.
Article in Diabetologia, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 69 citations in OpenAlex.
- Article
- Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis.Cellular & molecular biology letters · 2024Review
- Glucokinase Variant Proteins Are Resistant to Fasting-Induced Uridine Diphosphate Glucose-Dependent Degradation in Maturity-Onset Diabetes of the Young Type 2 Patients.International journal of molecular sciences · 2023Article
- A comprehensive map of human glucokinase variant activity.Genome biology · 2023Article
- Article
- Review
- The Human Islet: Mini-Organ With Mega-Impact.Endocrine reviews · 2021Review
- Functional Characterization of a Novel Heterozygous Mutation in the Glucokinase Gene That Causes MODY2 in Chinese Pedigrees.Frontiers in endocrinology · 2021Article
- Phenotypic and Genetic Heterogeneity in a Thai Glucokinase MODY Family Reveals the Complexity of Young-Onset Diabetes.Frontiers in endocrinology · 2021Article
- How Heterogeneity in Glucokinase and Gap-Junction Coupling Determines the Islet [CaBiophysical journal · 2019Article
- Targeted sequencing identifies novel variants in common and rare MODY genes.Molecular genetics & genomic medicine · 2019Article
- Identification of alkaline pH optimum of human glucokinase because of ATP-mediated bias correction in outcomes of enzyme assays.Scientific reports · 2019Article
- Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.Journal of diabetes investigation · 2019Article
- Conformational transition pathway of R308K mutant glucokinase in the presence of the glucokinase activator YNKGKA4.FEBS open bio · 2018Article
- Evidence-based tailoring of bioinformatics approaches to optimize methods that predict the effects of nonsynonymous amino acid substitutions in glucokinase.Scientific reports · 2017Article
- SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Identifying diabetes-related important protein targets with few interacting partners with the PageRank algorithm.Royal Society open science · 2015Article
- Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.Human molecular genetics · 2014Article
- De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed.Diabetologia · 2014Article
- Genetic variants, prediagnostic circulating levels of insulin-like growth factors, insulin, and glucose and the risk of colorectal cancer: the Multiethnic Cohort study.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2012Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisGlucokinase (GCK) acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. In the gene encoding GCK the heterozygous mutations that result in enzyme inactivation cause MODY2. Functional studies of naturally occurring GCK mutations associated with hyperglycaemia provide further insight into the biochemical basis of glucose sensor regulation. MATERIALS AND
methodsIdentification of GCK mutations in selected MODY patients was performed by single-strand conformation polymorphism and direct sequencing. The kinetic parameters and thermal stability of recombinant mutant human GCK were determined, and in pull-down assays the effect of these mutations on the association of GCK with glucokinase (hexokinase 4) regulator (GCKR, also known as glucokinase regulatory protein [GKRP]) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, also known as PFK2) was tested.
resultsWe identified three novel GCK mutations: the insertion of an asparagine residue at position 161 (inserN161) and two missense mutations (M235V and R308W). We also identified a fourth mutation (R397L) reported in a previous work. Functional characterisation of these mutations revealed that insertion of asparagine residue N161 fully inactivates GCK, whereas the M235V and R308W mutations only partially impair enzymatic activity. In contrast, GCK kinetics was almost unaffected by the R397L mutation. Although none of these mutations affected the interaction of GCK with PFKFB1, we found that the R308W mutation caused protein instability and increased the strength of interaction with GCKR. CONCLUSIONS/
interpretationOur results show that different MODY2 mutations impair GCK function through different mechanisms such as enzymatic activity, protein stability and increased interaction with GCKR, helping further elucidate the regulation of GCK activity.
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