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

2009 ◽  
Vol 174 (2) ◽  
pp. 534-540 ◽  
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

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

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1925-1931 ◽  
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.

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

Transfusion ◽  
2011 ◽  
Vol 52 (1) ◽  
pp. 7-13 ◽  
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

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

2022 ◽  
Vol 23 (2) ◽  
pp. 798
Author(s):  
Suvoshree Ghosh ◽  
Johannes Oldenburg ◽  
Katrin J. Czogalla-Nitsche
Keyword(s):  
Vitamin K ◽  
Treatment Strategies ◽  
Coagulation Factor ◽  
Matrix Gla Protein ◽  
Clotting Factors ◽  
Factor Deficiency ◽  
Coagulation Factor Deficiency ◽  
New Treatment ◽  
Deficiency Type

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.

scholarly journals Pseudoxanthoma Elasticum-Like Disorder with Multiple Coagulation Factor Deficiency in a Patient with Crohn’s Disease

2015 ◽  
Vol 89 (4) ◽  
pp. 474-477
Author(s):  
Byeong Zu Ghang ◽  
Ji Wan Lee ◽  
Jwa Hoon Kim ◽  
Yu Ri Seo ◽  
Min Chul Kim ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Coagulation Factor ◽  
Pseudoxanthoma Elasticum ◽  
Factor Deficiency ◽  
Coagulation Factor Deficiency

C0529: Hereditary Combined Vitamin K-Dependent Coagulation Factor Deficiency: Report of a New Case

2014 ◽  
Vol 133 ◽  
pp. S92
Author(s):  
M. Ángeles Dasí ◽  
S. Izquierdo ◽  
A. Moscardó ◽  
V. Vila ◽  
B. Argilés ◽  
...  
Keyword(s):  
Vitamin K ◽  
Coagulation Factor ◽  
Factor Deficiency ◽  
Coagulation Factor Deficiency

Congenital vitamin K-dependent coagulation factor deficiency: a case report

2005 ◽  
Vol 16 (7) ◽  
pp. 525-527 ◽  
Author(s):  
Jina Bhattacharyya ◽  
Pankhi Dutta ◽  
Pravas Mishra ◽  
Ashish Dixit ◽  
Upendra Srinivas ◽  
...  
Keyword(s):  
Case Report ◽  
Vitamin K ◽  
Coagulation Factor ◽  
Factor Deficiency ◽  
Coagulation Factor Deficiency

Compound Heterozygosity of a W493C Substitution and R704/Premature Stop Codon within the γ-Glutamyl Carboxylase in Combined Vitamin K-Dependent Coagulation Factor Deficiency in a French Family.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1302-1302 ◽  
Author(s):  
Dhouha Darghouth ◽  
Kevin W Hallgren ◽  
Odile Issertial ◽  
Amine Bazaa ◽  
Kathleen L Berkner ◽  
...  
Keyword(s):  
Control Patient ◽  
Vitamin K ◽  
Coagulation Factor ◽  
Expression Level ◽  
Factor V ◽  
Wild Type ◽  
Factor Deficiency ◽  
Family Analysis ◽  
Coagulation Factor Deficiency ◽  
Ggcx Gene

Abstract Abstract 1302 Poster Board I-324 Combined vitamin K-dependent (VKD) coagulation factor deficiency is an autosomal recessive bleeding disorder associated with defects in either the γ-carboxylase (GGCX) 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 due to mutations within either gene. Of note some mutations within the GGCX gene have recently been found associated with the pseudoxanthoma elasticum (PXE) syndrome, suggesting a role for GGCX in skin development. We report a new case of combined VKD coagulation factor deficiency resulting from two mutations in the GGCX gene, and the first identified in a French child, who exhibited impaired function in hemostatic VKD factors. The propositus exhibited bleeding at sites of venipuncture at birth, and at the age of 3 months was admitted in emergency for spontaneous multiple hematomas of the chest and thighs; recently, at the age of 1 year, he exhibited a hematoma of the wrist following a casual fall. Coagulation and VKD factors were low [PT (Control/patient): 12.8/>100 sec; II : 3 % ; VII :2% ; X :3%] while the non-VKD factor V was normal (105%). Vitamin K infusion corrected the bleeding tendency as well as coagulation paramenters [PT (Control/patient): 12.8/14.8 sec; II :72% ; VII+X : 62%; factor V remained normal at 102%]. Family analysis revealed that both parents and one brother were unaffected, both clinically and biologically, but that a brother had died of an unexplained abdominal hemorrhage, in the neonatal period. Taken together the clinical family history is consistent with a recessive trait. No sign of PXE was found in the family. DNA sequence analysis of the propositus did not identify any mutations in the VKORC1 gene but revealed two new heterozygous mutations in the carboxylase gene: a G10233T transversion in exon 11 (G1565U in mRNA) that caused an W493C substitution and a C12078T transition in the last exon (15) (C2196U in mRNA) that caused a premature R704stop, presumably deleting the last 55 C-terminal amino acids. W493 is a highly conserved amino acid and its homozygous mutation (for S493) has recently been reported in a case of VKD coagulation factor deficiency associated with PXE. R704 mutation has never been reported previously. Family analysis showed that W493C was transmitted by the father, R704stop by the mother, that the deceased brother carried both mutations, while the unaffected brother carried neither. Mutational analysis was carried out by site-directed mutagenesis of the GGCX cDNA subsequently subcloned into the BacPak8 baculovirus-based vector, and GGCX was expressed in the virally-infected SF21 insect cell line. Protein expression level of the enzyme was assessed by western blotting, and enzymatic activity was evaluated by measuring the incorporation of [14]C-CO2 within the Boc-Glu-Glu-Leu-OMe peptide. No difference in expression level was detected for either mutant protein compared to the wild type protein. However, while no difference in molecular weight was seen between the W493C mutant and wild type on wertern blotting, the R704stop mutation generated a shorter form of carboxylase than wild type, consistent with the predicted shorter reading frame. W493C mutant exhibited a much lower activity than wild type, suggesting a functional role for W493. The activity of the R704stop mutant is currently being assessed, as well as the activity of the coexpressed mutants. Since PXE has been correlated with a W493S mutation, a role for the W493C mutation in future development of PXE in this young patient will be assessed during follow-up. Disclosures No relevant conflicts of interest to declare.

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