The Role of GRP and MGP in the Development of Non-Hemorrhagic VKCFD1 Phenotypes

Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in blood coagulation, calcification, and cell signaling. Therefore, in addition to bleedings, some VKCFD1 patients develop diverse non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and/or cardiac defects. Recent studies showed that GGCX mutations differentially effect γ-carboxylation of VKD proteins, where clotting factors are sufficiently γ-carboxylated, but not certain non-hemostatic VKD proteins. This could be one reason for the development of diverse phenotypes. The major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients are mineralization defects. Therefore, the mechanism of regulation of calcification by specific VKD proteins as matrix Gla protein (MGP) and Gla-rich protein (GRP) in physiological and pathological conditions is of high interest. This will also help to understand the patho-mechanism of VKCFD1 phenotypes and to deduce new treatment strategies. In the present review article, we have summarized the recent findings on the function of GRP and MGP and how these proteins influence the development of non-hemorrhagic phenotypes in VKCFD1 patients.

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Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2

Nature ◽

10.1038/nature02214 ◽

2004 ◽

Vol 427 (6974) ◽

pp. 537-541 ◽

Cited By ~ 779

Author(s):

Simone Rost ◽

Andreas Fregin ◽

Vytautas Ivaskevicius ◽

Ernst Conzelmann ◽

Konstanze Hörtnagel ◽

...

Keyword(s):

Coagulation Factor ◽

Factor Deficiency ◽

Coagulation Factor Deficiency ◽

Warfarin Resistance ◽

Deficiency Type

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Treatment of vitamin K-dependent coagulation factor deficiency and subarachnoid hemorrhage

World Journal of Emergency Medicine ◽

10.5847/wjem.j.1920-8642.2011.01.014 ◽

2011 ◽

Vol 2 (1) ◽

pp. 73 ◽

Cited By ~ 1

Author(s):

Hai-fei Chen

Keyword(s):

Subarachnoid Hemorrhage ◽

Vitamin K ◽

Coagulation Factor ◽

Factor Deficiency ◽

Coagulation Factor Deficiency

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Co-Existent Pseudoxanthoma Elasticum and Vitamin K-Dependent Coagulation Factor Deficiency

American Journal Of Pathology ◽

10.2353/ajpath.2009.080865 ◽

2009 ◽

Vol 174 (2) ◽

pp. 534-540 ◽

Cited By ~ 43

Author(s):

Qiaoli Li ◽

Leon J. Schurgers ◽

Ann C.M. Smith ◽

Maria Tsokos ◽

Jouni Uitto ◽

...

Keyword(s):

Vitamin K ◽

Coagulation Factor ◽

Pseudoxanthoma Elasticum ◽

Factor Deficiency ◽

Coagulation Factor Deficiency

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Compound heterozygosity of novel missense mutations in the gamma-glutamyl-carboxylase gene causes hereditary combined vitamin K–dependent coagulation factor deficiency

Blood ◽

10.1182/blood-2005-12-010660 ◽

2006 ◽

Vol 108 (6) ◽

pp. 1925-1931 ◽

Cited By ~ 29

Author(s):

Dhouha Darghouth ◽

Kevin W. Hallgren ◽

Rebecca L. Shtofman ◽

Amel Mrad ◽

Youssef Gharbi ◽

...

Keyword(s):

Vitamin K ◽

Mutational Analysis ◽

Coagulation Factor ◽

Missense Mutations ◽

Compound Heterozygosity ◽

Wild Type ◽

Factor Deficiency ◽

Family Analysis ◽

Epoxide Reductase ◽

Coagulation Factor Deficiency

AbstractHereditary combined vitamin K–dependent (VKD) coagulation factor deficiency is an autosomal recessive bleeding disorder associated with defects in either the γ-carboxylase, which carboxylates VKD proteins to render them active, or the vitamin K epoxide reductase (VKORC1), which supplies the reduced vitamin K cofactor required for carboxylation. Such deficiencies are rare, and we report the fourth case resulting from mutations in the carboxylase gene, identified in a Tunisian girl who exhibited impaired function in hemostatic VKD factors that was not restored by vitamin K administration. Sequence analysis of the proposita did not identify any mutations in the VKORC1 gene but, remarkably, revealed 3 heterozygous mutations in the carboxylase gene that caused the substitutions Asp31Asn, Trp157Arg, and Thr591Lys. None of these mutations have previously been reported. Family analysis showed that Asp31Asn and Thr591Lys were coallelic and maternally transmitted while Trp157Arg was transmitted by the father, and a genomic screen of 100 healthy individuals ruled out frequent polymorphisms. Mutational analysis indicated wild-type activity for the Asp31Asn carboxylase. In contrast, the respective Trp157Arg and Thr591Lys activities were 8% and 0% that of wild-type carboxylase, and their compound heterozygosity can therefore account for functional VKD factor deficiency. The implications for carboxylase mechanism are discussed.

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VKCFD2 – from clinical phenotype to molecular mechanism

Hämostaseologie ◽

10.1055/s-0037-1617062 ◽

2016 ◽

Vol 36 (S 02) ◽

pp. S13-S20 ◽

Cited By ~ 1

Author(s):

K. J. Czogalla ◽

M. Watzka ◽

J. Oldenburg

Keyword(s):

Vitamin K ◽

Physiological Activity ◽

Coagulation Factors ◽

Clotting Factor ◽

Clotting Factors ◽

Vitamin K Cycle ◽

Factor Deficiency ◽

Er Retention ◽

Deficiency Type ◽

Diagnosis Therapy

SummaryVitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) is an enzyme essential for the vitamin K cycle. VKORC1 catalyses the reduction of vitamin K 2,3-epoxide to the quinone form of vitamin K and further to vitamin K hydroquinone. The generated vitamin K hydroquinone serves as substrate for the enzyme γ-glutamyl-carboxylase which modifies all vitamin K-dependent proteins, allowing them to bind calcium ions necessary for physiological activity. Vitamin K-dependent proteins include the coagulation factors FII, FVII, FIX, FX, and proteins C, S und Z. Insufficient VKORC1 enzyme activity results in deficiency of the vitamin K-dependent clotting factors leading to haemorrhagic disorders. This phenotype is known as vitamin K clotting factor deficiency type 2 (VKCFD2). Worldwide, only four families of independent origin have been reported with this rare bleeding disorder. Affected family members carry the mutation VKORC1:p.Arg98Trp in homozygous form, the only mutation found so far to be associated with VKCFD2. Now, ten years after the identification of the VKORC1 gene, the molecular pathomechanism of VKCFD2 has been clarified. The Arg98Trp mutation disrupts an ER retention motif of VKORC1 leading to mislocalisation of the protein to outside the endoplasmatic reticulum. In this review, we summarize the clinical data, diagnosis, therapy and molecular patho -mechanism of VKCFD2.

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Vitamin K-dependent coagulation factor deficiency in trauma: a comparative analysis between international normalized ratio and thromboelastography (CME)

Transfusion ◽

10.1111/j.1537-2995.2011.03237.x ◽

2011 ◽

Vol 52 (1) ◽

pp. 7-13 ◽

Cited By ~ 29

Author(s):

Bartolomeu Nascimento ◽

Mohammed Al Mahoos ◽

Jeannie Callum ◽

Antonio Capone ◽

Jennifer Pacher ◽

...

Keyword(s):

Comparative Analysis ◽

Vitamin K ◽

Coagulation Factor ◽

International Normalized Ratio ◽

Factor Deficiency ◽

Coagulation Factor Deficiency

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Acquired coagulation dysfunction resulting from vitamin K-dependent coagulation factor deficiency associated with rheumatoid arthritis: A case report

World Journal of Clinical Cases ◽

10.12998/wjcc.v10.i1.236 ◽

2022 ◽

Vol 10 (1) ◽

pp. 236-241

Author(s):

Yan-Jing Huang ◽

Liang Han ◽

Jing Li ◽

Chao Chen

Keyword(s):

Rheumatoid Arthritis ◽

Case Report ◽

Vitamin K ◽

Coagulation Factor ◽

Factor Deficiency ◽

Coagulation Factor Deficiency ◽

Coagulation Dysfunction

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Factor XI deficiency—resolving the enigma?

Hematology ◽

10.1182/asheducation-2009.1.97 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 97-105 ◽

Cited By ~ 44

Author(s):

Paula H. B. Bolton-Maggs

Keyword(s):

Side Effects ◽

Coagulation Factor ◽

Bleeding Tendency ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Factor Deficiency ◽

Coagulation Factor Deficiency ◽

Coagulation Pathway ◽

All Treatment

Abstract The management of factor XI deficiency is not straightforward for three reasons: firstly, the role of this factor in the coagulation pathway is not clearly understood; secondly, the bleeding tendency, although mild, is unpredictable and does not clearly relate to the factor XI level; and thirdly, all treatment products, although available, have some potentially serious side effects. These factors (or enigmas) contribute to the variable management of patients with this coagulation factor deficiency, but recent research is helping to clarify some of these areas.

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