ArticleHuman molecular genetics2014
Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 64 citations in OpenAlex.
- Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial.Nature medicine · 2022Trial
- Article
- Functional Characterization of Glucokinase Variants to Aid Clinical Interpretation of Monogenic Diabetes.International journal of molecular sciences · 2025Article
- Maturity onset diabetes of the young and beyond: the changing face of single-gene diabetes.European journal of endocrinology · 2025Review
- Case Report: New insights about clinical manifestations of patients withFrontiers in endocrinology · 2025Article
- Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis.Cellular & molecular biology letters · 2024Review
- Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts.Nature genetics · 2024Review
- Article
- The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients.International journal of molecular sciences · 2024Article
- Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.Genome biology · 2024Article
- The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.Communications medicine · 2023Article
- Monogenic diabetes.Nature reviews. Disease primers · 2023Review
- ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents.Pediatric diabetes · 2022Article
- How do I diagnose Maturity Onset Diabetes of the Young in my patients?Clinical endocrinology · 2022Review
- Frequency and spectrum of glucokinase mutations in an adult Maltese population.Acta diabetologica · 2022Article
- Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes.Genes · 2022Review
- 100 YEARS OF INSULIN: A brief history of diabetes genetics: insights for pancreatic beta-cell development and function.The Journal of endocrinology · 2021Review
- Recognition of maturity-onset diabetes of the young in China.Journal of diabetes investigation · 2021Article
- Monogenic diabetes: a gateway to precision medicine in diabetes.The Journal of clinical investigation · 2021Review
- Maturity-Onset Diabetes of the Young Identified Among Algerian Probands with Early-Onset Diabetes.Diabetes, metabolic syndrome and obesity : targets and therapy · 2020Article
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Authors and funding
17 authors at 7 institutions in 3 countries.
Funding
Abstract
Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.
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