Congenital Combined Deficiency of the Vitamin K-dependent Clotting Factors (VKCFD): A Novel Gamma-glutamyl Carboxylase (GGCX) Mutation

Absi, Hebah S. Al; Abdullah, Mohammad F.

doi:10.1097/mph.0000000000001385

Cited by 4 publications

(19 citation statements)

References 14 publications

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“…Type 1 and type 2 VKCFD, respectively, result from biallelic mutations in GGCX or VKORC1 (Table 3). GGCX encodes the γ‐glutamyl carboxylase that converts vitamin K hydroquinone (the reduced form) to vitamin K 2,3 epoxide (the oxidized form) 17,19 . VKORC1 encodes the vitamin K 2,3‐epoxide reductase complex (VKORC) that regenerates reduced vitamin K for γ‐carboxylation of vitamin K‐dependent proteins 17,19,20 …”

Section: Familial Vitamin K‐dependent Clotting Factor Deficiencymentioning

confidence: 99%

“… 18 Symptoms can include: easy bruising, prolonged bleeding from minor wounds, epistaxis, gingival bleeding, HMB, postpartum bleeding, postoperative bleeding, gastrointestinal bleeding, hemarthrosis, and hemoperitoneum following ovarian cyst rupture (Table 3). 17–20 Thrombosis has only been anecdotally suspected in VKCFD, 21 indicating that the factor deficiencies likely outweigh thrombotic risks from the anticoagulant protein deficiencies. As VKCFD affects some vitamin‐K dependent non‐hemostatic proteins, there can be ophthalmic, cardiac, dermatologic, and in particular, orthopedic manifestations 19,20 .…”

Section: Familial Vitamin K‐dependent Clotting Factor Deficiencymentioning

confidence: 99%

“…Severe intracranial hemorrhages pose the greatest risk to patients with VKCFD 18 . Following diagnosis of VKCFD, vitamin K prophylaxis and as‐needed treatment allow affected persons to lead healthy and productive lives 19 …”

Section: Familial Vitamin K‐dependent Clotting Factor Deficiencymentioning

confidence: 99%

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Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Mathews

Tasneem

Hayward

2023

Int J Lab Hematology

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Background Coagulation factors, anticoagulants, and fibrinolytic proteins are important for hemostasis, and mutations affecting these proteins causes some rare inherited bleeding disorders that are particularly challenging to diagnose. Aims This review provides current information on rare inherited bleeding disorders that are difficult to diagnose. Material & Methods A review of the literature was conducted for up to date information on rare and difficult to diagnose bleeding disorders. Results Some rare bleeding disorders cause an inherited deficiency of multiple coagulation factors (F), such as combined FV and FVIII deficiency and familial vitamin K‐dependent clotting factor deficiency. Additionally, congenital disorders of glycosylation can affect a variety of procoagulant and anticoagulant proteins and also platelets. Some bleeding disorders reflect mutations with unique impairments in the procoagulant/anticoagulant balance, including those caused by F5 mutations that secondarily increase the plasma levels of tissue factor pathway inhibitor as well as THBD mutations that increase functional thrombomodulin in plasma or cause a consumptive coagulopathy due to thrombomodulin deficiency. Some bleeding disorders accelerate fibrinolysis due to loss‐of‐function mutations in SERPINE1 and SERPINF2 or in the case of Quebec platelet disorder, a duplication mutation that rewires PLAU and selectively increases expression in megakaryocytes, resulting in a unique platelet‐dependent gain‐of‐function defect in fibrinolysis. Discussion Current information on rare and difficult to diagnose bleeding disorders indicates they have unique clinical and laboratory features, and pathogenic characteristics to consider for diagnostic evaluation. Conclusion Laboratories and clinicians should consider rare inherited disorders, and difficult to diagnose conditions, in their strategy for diagnosing bleeding disorders.

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Section: Familial Vitamin K‐dependent Clotting Factor Deficiencymentioning

confidence: 99%

Section: Familial Vitamin K‐dependent Clotting Factor Deficiencymentioning

confidence: 99%

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Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Mathews

Tasneem

Hayward

2023

Int J Lab Hematology

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“…Currently, more than 40 GGCX mutations have been identified from patients with vitamin K-related disorders. 17,34,35 These mutations are scattered throughout the GGCX molecule (Figure 2A).…”

Section: Ggcx Mutations Differentially Affect Carboxylation Of the 3 Reporter Proteinsmentioning

confidence: 99%

“…5,[30][31][32][33] Genetic screenings of patients with vitamin K-related disorders have identified more than 40 naturally occurring mutations in GGCX. 17,34,35 Clinical manifestations of these mutations have been classified into 5 distinct phenotypes: the bleeding phenotype (VKCFD) and the nonbleeding phenotypes of cardiac, dermatologic, ophthalmologic, and osseous symptoms. 17 VKCFD results from insufficient carboxylation of VKD coagulation factors in the liver and can be ameliorated through the administration of high doses of vitamin K. 15 However, nonbleeding phenotypes, caused by defects in carboxylation of extrahepatic Gla proteins, seem to be more difficult to rescue and require much higher doses of vitamin K. 25,36 Importantly, some GGCX-associated nonbleeding phenotypes (eg, osseous symptoms) overlap clinically with other syndromes, such as the fetal warfarin syndrome (an embryo disorder resulting from fetal exposure to maternal ingestion of warfarin during pregnancy).…”

Section: Introductionmentioning

confidence: 99%

γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K–dependent proteins

Hao

Jin

Chen

et al. 2021

Blood

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Gamma-glutamyl carboxylase (GGCX) is an integral membrane protein that catalyzes posttranslational carboxylation of a number of vitamin K-dependent (VKD) proteins involved in a wide variety of physiological processes, including blood coagulation, vascular calcification, and bone metabolism. Naturally occurring GGCX mutations are associated with multiple distinct clinical phenotypes. However, the genotype-phenotype correlation of GGCX remains elusive. Here, we systematically examined the effect of all naturally occurring GGCX mutations on the carboxylation of three structure-function distinct VKD proteins in a cellular environment. GGCX mutations were transiently introduced into GGCX-deficient human embryonic kidney 293 cells stably expressing chimeric coagulation factor, matrix Gla protein (MGP), or osteocalcin as VKD reporter-proteins, then the carboxylation efficiency of these reporter-proteins were evaluated. Our results show that GGCX mutations differentially affect the carboxylation of these reporter-proteins and the efficiency of using vitamin K as a cofactor. Carboxylation of these reporter-proteins by a C-terminal truncation mutation (R704X) implies that GGCX's C-terminus plays a critical role in the binding of osteocalcin, but not in the binding of coagulation factors and MGP. This has been confirmed by probing the protein-protein interaction between GGCX and its protein substrates in live cells using bimolecular fluorescence complementation and chemical cross-linking assays. Additionally, using a minigene splicing assay, we demonstrated that several GGCX missense mutations affect GGCX's pre-mRNA splicing rather than altering the corresponding amino acid residues. Results from this study interpreted the correlation of GGCX's genotype and its clinical phenotypes, and clarified why vitamin K administration rectified bleeding disorders but not non-bleeding disorders.

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Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K–Dependent Coagulation Factors Deficiency

Perrone,

Raso,

Napolitano

2024

Semin Thromb Hemost

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Vitamin K–dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K–dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in γ-glutamyl-carboxylase (GGCX) or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous GGCX gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of GGCX and VKORC1 mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations.

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Congenital Combined Deficiency of the Vitamin K-dependent Clotting Factors (VKCFD): A Novel Gamma-glutamyl Carboxylase (GGCX) Mutation

Cited by 4 publications

References 14 publications

Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K–dependent proteins

Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K–Dependent Coagulation Factors Deficiency

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