ArticleThe Biochemical journal2006
Effects of novel maturity-onset diabetes of the young (MODY)-associated mutations on glucokinase activity and protein stability.
Article in The Biochemical journal, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 55 citations in OpenAlex.
- Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial.Genetics in medicine : official journal of the American College of Medical Genetics · 2018 · on this mapTrial
- The Genetic Landscape of Diabetes Mellitus: Lessons from Monogenic and Polygenic Forms.Life (Basel, Switzerland) · 2026Review
- Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis.Cellular & molecular biology letters · 2024Review
- The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients.International journal of molecular sciences · 2024Article
- Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes andJournal of clinical research in pediatric endocrinology · 2024Article
- 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
- From glucose sensing to exocytosis: takes from maturity onset diabetes of the young.Frontiers in endocrinology · 2023Review
- Diabetic Kinome Inhibitors-A New Opportunity for β-Cells Restoration.International journal of molecular sciences · 2021Review
- A novel reverse two-hybrid method for the identification of missense mutations that disrupt protein-protein binding.Scientific reports · 2020Article
- The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY).Clinical diabetes and endocrinology · 2020Review
- Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research.Frontiers in endocrinology · 2020Review
- How Heterogeneity in Glucokinase and Gap-Junction Coupling Determines the Islet [CaBiophysical journal · 2019Article
- Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.Journal of diabetes investigation · 2019Article
- Molecular and cellular regulation of human glucokinase.Archives of biochemistry and biophysics · 2019Review
- Genetic Testing of Maturity-Onset Diabetes of the Young Current Status and Future Perspectives.Frontiers in endocrinology · 2018Review
- Lack of glibenclamide response in a case of permanent neonatal diabetes caused by incomplete inactivation of glucokinase.JIMD reports · 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
- Reclassification of diabetes etiology in a family with multiple diabetes phenotypes.The Journal of clinical endocrinology and metabolism · 2014Article
- Normal glucose metabolism in carnivores overlaps with diabetes pathology in non-carnivores.Frontiers in endocrinology · 2013Review
- GCK Mutation in a Child with Maturity Onset Diabetes of the Young, Type 2.Iranian journal of pediatrics · 2013Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glucokinase acts as the pancreatic glucose sensor and plays a critical role in the regulation of insulin secretion by the beta-cell. Heterozygous mutations in the glucokinase-encoding GCK gene, which result in a reduction of the enzymatic activity, cause the monogenic form of diabetes, MODY2 (maturity-onset diabetes of the young 2). We have identified and functionally characterized missense mutations in the GCK gene in diabetic families that result in protein mutations Leu165-->Phe, Glu265-->Lys and Thr206-->Met. The first two are novel GCK mutations that co-segregate with the diabetes phenotype in their respective families and are not found in more than 50 healthy control individuals. In order to measure the biochemical effects of these missense mutations on glucokinase activity, we bacterially expressed and affinity-purified islet human glucokinase proteins carrying the respective mutations and fused to GST (glutathione S-transferase). Enzymatic assays on the recombinant proteins revealed that mutations Thr206-->Met and Leu165-->Phe strongly affect the kinetic parameters of glucokinase, in agreement with the localization of both residues close to the active site of the enzyme. In contrast, mutation Glu265-->Lys, which has a weaker effect on the kinetics of glucokinase, strongly affects the protein stability, suggesting a possible structural defect of this mutant protein. Finally, none of the mutations tested appears to affect the interaction of gluco-kinase with the glucokinase regulatory protein in the yeast two-hybrid system.
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