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.

Prevalence of Coagulation Factors Deficiency among Young Adults in Saudi Arabia: A National Survey

Introduction Inherited bleeding disorders vary in prevalence due to genetic disparity and ethnicity. Little is known about the prevalence of coagulation factor deficiency and bleeding disorders in middle-eastern population. Methods Young Saudi adults with at least one positive bleeding symptom reported in semi-structured validated condensed MCMDM-1vWD questionnaire were tested for complete blood count, routine and special coagulation tests, serum ferritin level, and capillary zone electrophoresis. After initial testing, those with prolonged prothrombin time (PT) or activated prothrombin time (APTT) had further testing to evaluate coagulation factors level. Platelet function was tested through platelet function analyzer (PFA)-100, and multiplate aggregometer (MEA) on patients suspected of having platelet disorders. Results Six-hundred-forty patients (male = 347, 54.2%) were included. A possible platelet function defect was diagnosed in three patients with one matching Glanzmann's thrombasthenia trait pattern, and one that of Bernard-Soulier trait pattern. One patient was diagnosed with von Willebrand disease. Deficiencies in coagulation factor levels were revealed as F-VIII in 14 (7.4%), F-IX in 15 (7.6%), F-II in two (3.3%), F-V in 17 (26.1%), FVII in two (3.1%), and F-X in one (1.8%) of study subjects; low vWF activity (<50%) was found in 14 (8%). Abnormal values were found for various laboratory tests with prolongation of platelet function analyzer-epinephrine (PFA-EPI) in 11%, PFA-ADP or arachidonic acid in 15.2%, PT in 35.9%, and APTT in 63.7%. Five-hundred-seventy-six patients (90%) had normal results in the coagulation factor assays and were categorized as patients with bleeding of unknown cause (BUC). A diagnosis of a bleeding disorder was more frequently made in men than in women (38 vs. 26). Iron deficiency anemia was found in 18 (25%) females positively associated with F-IX deficiency (p-value 0.000). Male gender (73.3%, p = 0.007) was independently associated with the diagnosis of coagulation factor deficiency. Conclusion The current study reports a higher prevalence of coagulation factors deficiency in Saudi population than reported in the western population.

Crystallographic snapshots of the EF-hand protein MCFD2 complexed with the intracellular lectin ERGIC-53 involved in glycoprotein transport

The transmembrane intracellular lectin ER–Golgi intermediate compartment protein 53 (ERGIC-53) and the soluble EF-hand multiple coagulation factor deficiency protein 2 (MCFD2) form a complex that functions as a cargo receptor, trafficking various glycoproteins between the endoplasmic reticulum (ER) and the Golgi apparatus. It has been demonstrated that the carbohydrate-recognition domain (CRD) of ERGIC-53 (ERGIC-53CRD) interacts with N-linked glycans on cargo glycoproteins, whereas MCFD2 recognizes polypeptide segments of cargo glycoproteins. Crystal structures of ERGIC-53CRD complexed with MCFD2 and mannosyl oligosaccharides have revealed protein–protein and protein–sugar binding modes. In contrast, the polypeptide-recognition mechanism of MCFD2 remains largely unknown. Here, a 1.60 Å resolution crystal structure of the ERGIC-53CRD–MCFD2 complex is reported, along with three other crystal forms. Comparison of these structures with those previously reported reveal that MCFD2, but not ERGIC-53–CRD, exhibits significant conformational plasticity that may be relevant to its accommodation of various polypeptide ligands.