ArticleThe Journal of clinical investigation2012
Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes.
Article in The Journal of clinical investigation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 3 syntheses or guidelines pooled it, 46 citations in OpenAlex.
- Mendelian pathway analysis of laboratory traits reveals distinct roles for ciliary subcompartments in common disease pathogenesis.American journal of human genetics · 2021Pooled it
- Association of type 2 diabetes susceptible genes GCKR, SLC30A8, and FTO polymorphisms with gestational diabetes mellitus risk: a meta-analysis.Endocrine · 2018Pooled it
- Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.PLoS genetics · 2015Pooled it
- Glucokinase activity suppresses hepatic cholesterol synthesis and triglyceride accumulation: A new model for the effects of the GKRP P466L common human variant.Molecular metabolism · 2026Article
- Glucokinase activity suppresses hepatic cholesterol synthesis and triglyceride accumulation: A new model for the effects of the GKRP P466L common human variant.bioRxiv : the preprint server for biology · 2026Article
- Cornea Arcus and Dyslipidemia in Unrelated Adults With Monoallelic Germline Variants in theClinical medicine insights. Endocrinology and diabetes · 2026Article
- Significant Association Between Glucokinase Regulatory Protein Variants and Genetic and Metabolic Diseases.Current issues in molecular biology · 2025Review
- Pathogenic variation in insulin resistance genes is common in polycystic ovary syndrome (PCOS): a strategy for causal gene discovery using whole-exome sequencing (WES) in complex traits.medRxiv : the preprint server for health sciences · 2025Article
- Genomics and multiomics in the age of precision medicine.Pediatric research · 2025Review
- Current Insight on the Role of Glucokinase and Glucokinase Regulatory Protein in Diabetes.Mini reviews in medicinal chemistry · 2024Review
- Genotype first: Clinical genomics research through a reverse phenotyping approach.American journal of human genetics · 2023Review
- Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD.Frontiers in endocrinology · 2023Review
- Frequencies of variants in genes associated with dyslipidemias identified in Costa Rican genomes.Frontiers in genetics · 2023Article
- Pleiotropic Effects of Common and RareGenes · 2022Article
- Case report: Genomic screening for inherited cardiac conditions in Ecuadorian mestizo relatives: Improving familial diagnose.Frontiers in cardiovascular medicine · 2022Article
- Evidence-based tailoring of bioinformatics approaches to optimize methods that predict the effects of nonsynonymous amino acid substitutions in glucokinase.Scientific reports · 2017Article
- Human genetics as a model for target validation: finding new therapies for diabetes.Diabetologia · 2017Review
- Differential analysis of mutations in the Jewish population and their implications for diseases.Genetics research · 2017Article
- Type 1 Hyperlipoproteinemia Due to Compound Heterozygous Rare Variants in GCKR.The Journal of clinical endocrinology and metabolism · 2016Article
- Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.American journal of human genetics · 2016Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene- and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missense variant p.Pro446Leu, all variants were rare in the cohort. Accordingly, we functionally characterized all variants to evaluate their potential phenotypic effects. Defects were observed for the majority of the rare variants after assessment of cellular localization, ability to interact with GCK, and kinetic activity of the encoded proteins. Comparing the individuals with functional rare variants to those without such variants showed associations with lipid phenotypes. Our findings suggest that, while nonsynonymous GCKR variants, excluding p.Pro446Leu, are rare in individuals of mixed European descent, the majority do affect protein function. In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.