ArticleBlood2016
Characterization of vitamin K-dependent carboxylase mutations that cause bleeding and nonbleeding disorders.
Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 2 of them syntheses that pooled it.
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37 citing papers in PubMed, 2 syntheses or guidelines pooled it, 57 citations in OpenAlex.
- Recommendations for Clinical Warfarin Genotyping Allele Selection: A Report of the Association for Molecular Pathology and the College of American Pathologists.The Journal of molecular diagnostics : JMD · 2020Guideline
- GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations.International journal of molecular sciences · 2017Pooled it
- Systematic Identification of Therapeutic Targets and Repurposed Drugs for Stroke: From Genome Causal Analysis to Multilevel Validation.Journal of the American Heart Association · 2026Article
- Small-molecule inhibition of γ-glutamyl carboxylase reveals a novel anticoagulant strategy.Blood advances · 2026Article
- Multi-trait and Gene-Based Analyses Identify Genetic Variants Associated with Spontaneous Coronary Artery Dissection.medRxiv : the preprint server for health sciences · 2026Article
- Structural and functional insights into γ-glutamyl carboxylase-factor IX interaction: implications for vitamin K-dependent bleeding disorders.Haematologica · 2026Article
- Molecular insights into the comorbidity of vitamin K-dependent clotting factor deficiency and chondrodysplasia punctata.Journal of thrombosis and haemostasis : JTH · 2025Article
- Structural insight into bicarbonate-mediated carboxylation by human vitamin K-dependent carboxylase.Nature communications · 2025Article
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- Article
- Mechanisms of Vitamins Inhibiting Ferroptosis.Antioxidants (Basel, Switzerland) · 2024Review
- Assessment of gamma-glutamyl carboxylase activity in its native milieu.Methods in enzymology · 2024Article
- Inorganic pyrophosphate plasma levels in patients with GGCX-associated PXE-like phenotypes.Frontiers in genetics · 2024Article
- Characterization of Gla proteoforms and non-Gla peptides of gamma carboxylated proteins: Application to quantification of prothrombin proteoforms in human plasma.Analytica chimica acta · 2023Article
- A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase.Nature communications · 2023Article
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- Vitamin K-Dependent Protein Activation: Normal Gamma-Glutamyl Carboxylation and Disruption in Disease.International journal of molecular sciences · 2022Review
- Naturally occurring UBIAD1 mutations differentially affect menaquinone biosynthesis and vitamin K-dependent carboxylation.The FEBS journal · 2022Article
- The Role of GRP and MGP in the Development of Non-Hemorrhagic VKCFD1 Phenotypes.International journal of molecular sciences · 2022Review
- Calcium Homeostasis in the Epididymal Microenvironment:Frontiers in cell and developmental biology · 2022Review
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6 authors at 4 institutions in 3 countries.
Funding
Abstract
Vitamin K-dependent coagulation factors deficiency is a bleeding disorder mainly associated with mutations in γ-glutamyl carboxylase (GGCX) that often has fatal outcomes. Some patients with nonbleeding syndromes linked to GGCX mutations, however, show no coagulation abnormalities. The correlation between GGCX genotypes and their clinical phenotypes has been previously unknown. Here we report the identification and characterization of novel GGCX mutations in a patient with both severe cerebral bleeding disorder and comorbid Keutel syndrome, a nonbleeding malady caused by functional defects of matrix γ-carboxyglutamate protein (MGP). To characterize GGCX mutants in a cellular milieu, we established a cell-based assay by stably expressing 2 reporter proteins (a chimeric coagulation factor and MGP) in HEK293 cells. The endogenous GGCX gene in these cells was knocked out by CRISPR-Cas9-mediated genome editing. Our results show that, compared with wild-type GGCX, the patient's GGCX D153G mutant significantly decreased coagulation factor carboxylation and abolished MGP carboxylation at the physiological concentration of vitamin K. Higher vitamin K concentrations can restore up to 60% of coagulation factor carboxylation but do not ameliorate MGP carboxylation. These results are consistent with the clinical results obtained from the patient treated with vitamin K, suggesting that the D153G alteration in GGCX is the causative mutation for both the bleeding and nonbleeding disorders in our patient. These findings provide the first evidence of a GGCX mutation resulting in 2 distinct clinical phenotypes; the established cell-based assay provides a powerful tool for studying the clinical consequences of naturally occurring GGCX mutations in vivo.
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