1/49. Factor XII Tenri, a novel cross-reacting material negative factor xii deficiency, occurs through a proteasome-mediated degradation.A homozygous cross-reacting material negative factor XII-deficient patient with 3% antigen and activity levels of factor XII was screened for the identification of a mutation at the genomic level. Low-ionic strength single-stranded conformation polymorphism (SSCP) analysis and sequence analysis showed that the proband's gene for factor XII had an A-->G substitution at nucleotide position 7832 in exon 3, resulting in a Tyr34 to Cys substitution in the NH2-terminal type II domain of factor XII. We designated this mutation as factor XII Tenri. Mutagenic polymerase chain reaction (PCR), followed by KpnI digestion, showed a homozygous mutation in the proband's gene and heterozygous mutations in his parents and sister. immunoprecipitation and Western blot analyses of plasma samples from the factor XII Tenri family indicated that the proband had a trace amount of variant factor XII with an apparent molecular mass of 115 kD, which was converted to the normal 80-kD form after reduction, suggesting that factor XII Tenri was secreted as a disulfide-linked heterodimer with a approximately 35-kD protein, which we identified as alpha1-microglobulin by immunoblotting. pulse-chase experiments using baby hamster kidney (BHK) cells showed that Tenri-type factor XII was extensively degraded intracellularly, but the addition of cystine resulted in increased secretion of the mutant. Using membrane-permeable inhibitors, we observed that the degradation occurred in the pre-Golgi, nonlysosomal compartment and a proteasome appeared to play a major role in this process. On the basis of these in vitro results, we speculate that the majority of the factor XII Tenri is degraded intracellularly through a quality control mechanism in the endoplasmic reticulum (ER), and a small amount of factor XII Tenri that formed a disulfide-linked heterodimer with alpha1-microglobulin is secreted into the blood stream.- - - - - - - - - - ranking = 1keywords = deficiency, protein (Clic here for more details about this article) |
2/49. Symptomatic combined homozygous factor xii deficiency and heterozygous factor v Leiden. [email protected].A family with a combined deficiency of factor XII and factor v Leiden is presented. The proposita is a 72-year-old who showed a mild to moderate thrombotic tendency characterized by two episodes of deep venous thrombosis and superficial phlebitis between the age of 50 and 71. She was shown to be carrier of homozygous factor xii deficiency and heterozygous FV Leiden mutation. A sister of the proposita showed the same pattern but remained asymptomatic. Other family members showed either isolated heterozygous factor xii deficiency or combined heterozygous factor xii deficiency and heterozygous FV Leiden mutation but were all asymptomatic. These data lend support to those who maintain that FV Leiden is a mild genetic determinant for thrombosis. The role of FXII deficiency as an additional risk factor remains questionable.- - - - - - - - - - ranking = 2.24854782209keywords = deficiency (Clic here for more details about this article) |
3/49. Is factor xii deficiency related to recurrent miscarriage?Factor XII (FXII) is an important protease that plays a major role in the initiation of the intrinsic pathway of blood coagulation. Although congenital FXII deficiency is not associated with a clinical bleeding tendency, it can be identified on a routine coagulation test, such as a prolonged activated partial thromboplastin time. This deficiency is a rare autosomal recessive disorder. It is still unclear whether FXII deficiency causes any disorders during pregnancy. Recurrent miscarriages and placental abruption were reported in cases with FXII deficiency. We successfully treated a woman whose pregnancy was complicated by congenital FXII deficiency. We report her clinical courses of gestation, delivery, and puerperium and discuss the role of maternal FXII associated with pregnancy. In our case, courses of gestation and delivery were normal. Postpartum uterine bleeding was, however, prolonged due to a subinvolution of the puerperal uterus. Our results indicate that, except for postpartum uterine contraction, FXII does not play a major role in gestation and delivery. We suggest that FXII deficiency is not associated with recurrent miscarriage and that normal gestation and vaginal delivery are possible even in cases with congenital FXII deficiency. We assert that the possible correlation of FXII deficiency with recurrent miscarriage merits reevaluation.- - - - - - - - - - ranking = 2.9980637627867keywords = deficiency (Clic here for more details about this article) |
4/49. aortic valve replacement in a patient with factor xii deficiency: case report.Congenital factor xii deficiency is a rare condition. We report a case of aortic valve replacement (AVR) in a 63-year-old man with factor xii deficiency. On admission, the patient's activated partial thromboplastin time (aPTT) was prolonged (271 s), and activated clotting time was 500 s. His factor XII level was <3%. The Sonoclot signature showed an abnormal pattern. AVR with a prosthetic valve (St. Jude Medical) was performed safely after the normalization of aPTT and the Sonoclot signature by frozen plasma transfusion. The perioperative management in patients with factor xii deficiency is discussed.- - - - - - - - - - ranking = 1.7488705282922keywords = deficiency (Clic here for more details about this article) |
5/49. [Ischemic stroke in a patient with factor XII (Hageman) deficiency]Unlike most other coagulation factor deficiencies, usually associated with abnormal bleeding, lack of factor XII (Hageman) can result in thromboembolic events as a result of a deficient fibrinolytic system. We report a patient with an ischemic stroke and factor xii deficiency, a rare hereditary disorder. The optimal therapy for these uncommon disorders is not well established, but they probably require long term anticoagulation to prevent subsequent thrombotic events.- - - - - - - - - - ranking = 1.2491932344945keywords = deficiency (Clic here for more details about this article) |
6/49. Identification and characterization of two novel mutations (Q421 K and R123P) in congenital factor xii deficiency.The factor XII genes of two unrelated factor XII-deficient Japanese families were screened, and two novel mutations were identified. A heterozygous mutation (Q421K) was identified in the gene of a cross-reacting material (CRM)-negative patient with reduced FXII activity (entitled Case 1). No mutations were discovered in the other allele. Case 2 was a CRM-negative patient with severe FXII deficiency. In this case, a homozygous mutation (R123P) was discerned. Expression studies in Chinese Hamster ovary (CHO) cells demonstrated accumulation of mutant Q421 K factor XII in the cell, and insufficient secretion, while the R123P mutant showed lower levels of accumulation than wild-type, and no evidence of secretion in culture supernatant. In the presence of proteasome inhibitor, all types of FXII (wild-type. Q421K, R123P) accumulated in the cells. Protease protection experiments using the microsomal fraction of these cell lines demonstrated that while 20% wild-type FXII (total wild-type:100%) and 10% R123P mutant (total R123P-type: 40%) were resistant to treatment with trypsin, 50% Q421K-type FXII (total Q421K-type:130%) remained resistant to digestion. From these results, we conclude that Q421K is less susceptible to proteasome degradation than wild-type, but is unable to exit the ER efficiently, resulting in insufficient secretion phenotype. In contrast, R123P is susceptible to proteasome degradation and is not secreted.- - - - - - - - - - ranking = 1.2491932344945keywords = deficiency (Clic here for more details about this article) |
7/49. Huge left atrial thrombus with mitral stenosis in congenital factor xii deficiency.factor xii deficiency has been reported to be a risk factor for thromboembolism as a result of inactivation of fibrinolysis. We describe a case of a huge left atrial thrombus with mitral stenosis, which was successfully removed surgically in a Factor XII deficient patient.- - - - - - - - - - ranking = 1.2491932344945keywords = deficiency (Clic here for more details about this article) |
8/49. Molecular characterization of coagulation factor xii deficiency in a Japanese family.We report the identification in a Japanese family of a novel homozygous W486C mutation in the protease domain of coagulation factor XII (FXII), which was associated with the reduction of plasma FXII activity and antigen level to less than 5% of normal. Sequences of each exon for FXII gene was analysed in family members by polymerase chain reaction (PCR) amplification followed by a direct sequencing method. sequence analysis showed a homozygous substitution of G to C at nucleotide position 10587 (cDNA position 1458) in proband's FXII gene, resulting in a Trp to Cys substitution in the catalytic domain of FXII. PCR-fragment length polymorphism analysis of 55 healthy volunteers showed no such mutation. Transient expression of FXII in HK-293T cells and analysis of FXII antigen in culture media and cell lysates showed reduced secretion of mutant protein by more than 84% relative to that of wild type protein although the intracellular contents were similar. Our results suggest that the reduced secretion of FXII protein was due to incorrect folding caused by the introduction of Cys486. We designated this mutation as FXII Mie-1.- - - - - - - - - - ranking = 1.0012908248089keywords = deficiency, protein (Clic here for more details about this article) |
9/49. Behcet's syndrome and factor xii deficiency.Several mechanisms have been proposed to explain thrombotic tendency in Behcet's syndrome. We report the case of a 43-year old woman presenting retinal-vein thrombosis, factor xii deficiency and Behcet's syndrome. This kind of association has thus far never been reported. factor xii deficiency is known to possibly induce various types of thrombosis and might explain the prevalence of ocular symptoms in our patient.- - - - - - - - - - ranking = 1.4990318813933keywords = deficiency (Clic here for more details about this article) |
10/49. Genetic analyses and expression studies identified a novel mutation (W486C) as a molecular basis of congenital coagulation factor xii deficiency.We analyzed the factor XII (FXII) gene of a patient with congenital FXII deficiency and identified a novel amino acid substitution (W486C) in the catalytic domain. The proband was an asymptomatic 49-year-old Japanese female with abnormal coagulation test, discovered by chance. The FXII activity and antigen level were both under 10%, suggesting a cross-reacting material-negative FXII deficiency. sequence analysis of the proband's FXII gene revealed a homozygous nucleotide substitution G --> C in exon 12, resulting in the amino acid substitution W486C in the catalytic domain. We constructed the mutant FXII cDNA in an expression plasmid vector and transfected it into Chinese hamster ovary cells. The recombinant wild-type FXII antigen was detected in the culture medium by immunoprecipitation assay, but the mutant FXII (W486C) was not observed. On the other hand, both the wild-type FXII and W486C cell lysates contained FXII antigen and FXII mRNA, as estimated by western blotting and quantitative reverse transcriptase-polymerase chain reaction. These findings suggest that the W486C substitution of FXII impairs intracellular processing of the protein and/or transport system.- - - - - - - - - - ranking = 1.4996772937978keywords = deficiency, protein (Clic here for more details about this article) |
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