Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A dysfunctional protein C (PC) molecule (Protein C Padua 2) was found in a 40-year-old man presenting with recurrent deep vein thrombosis/pulmonary embolism and a family history of thrombotic disease. The patient exhibited a normal PC antigen level, normal chromogenic activity (using Protac as PC activator) but markedly reduced coagulometric activity. After adsorption of patient plasma onto Al(OH)3, between 30% and 45% PC antigen/chromogenic activity but no coagulometric activity was detectable in the supernatant. The dysfunctional molecule exhibited reduced affinity for a Ca++ dependent anti-protein C monoclonal antibody as detected by specific ELISA assay. Immunoblotting experiments showed that PC Padua 2 had an increased MW (95 kD v 65 kD for normal PC). The lesion responsible was determined by PCR/direct sequencing to be a heterozygous CGT/TGT transition in exon 3 of the protein C gene resulting in the substitution of Arg by Cys at residue--1 in the pro-peptide leader sequence. The presence of a high MW PC was consistent with the fact that (part of) the propeptide (at least Cys-1) still was attached to the protein C molecule. This finding could also explain the strongly reduced affinity of PC Padua 2 for the Ca++ dependent anti-protein C monoclonals.
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PMID:A novel dysfunctional protein C (protein C Padua 2) associated with a thrombotic tendency: substitution of Cys for Arg-1 results in a strongly reduced affinity for binding of Ca++. 813 74

Medulloblastoma is a malignant, invasive embryonal tumour of the cerebellum which manifests preferentially in children. A subset of cases is associated with colon cancer and APC germline mutations (Turcot syndrome), and APC and beta-catenin point mutations occur in up to 10% of sporadic cases, indicating the involvement of the Wnt pathway in the development of medulloblastoma. In 39 sporadic cerebellar medulloblastomas screeened for alterations in the AXIN1 gene, another component of the Wnt pathway, we found missense AXIN1 mutations in two tumours, CCC-->TCC at codon 255 (exon 1, Pro-->Ser) and TCT-->TGT at codon 263 (exon 1, Ser-->Cys). Furthermore, the A allele at the G/A polymorphism at nucleotide 16 in intron 4 was significantly over-represented in medulloblastomas (39 cases; G 0.76 vs-A 0.24) compared to healthy individuals (86 cases; G 0.91 vs A 0.09; P=0.0027). RT-PCR revealed large deletions in the AXIN1 gene in 5/12 (42%) medulloblastomas, consistent with a previous report. However, we observed such deletions at a similar frequency also in normal brain tissue (6/12, 50%). Since there are multiple complementary, inverted sequences present in the AXIN1 gene, these large deletions may represent RT-PCR errors due to stem-loop secondary structures.
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PMID:AXIN1 mutations but not deletions in cerebellar medulloblastomas. 1255 76

Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.
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PMID:Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. 1463 73

Despite knowledge of various inherited risk factors associated with venous thromboembolism (VTE), no definite cause can be found in about 50% of patients. The lack of an intermediate phenotype in VTE impedes the discovery of new familial risk factors. We set out to define an intermediate phenotype for VTE by performing global coagulation analyses in unexplained thrombophilic families. Families were selected through a proband with VTE but without one of the known thrombophilic defects and at least one 1st or two 2nd degree family members with VTE. Clinical data were collected using a standardized questionnaire. Blood samples were collected for overall haemostasis assays (i.e. thrombin generation time [TGT], endogenous thrombin potential [ETP], prothrombin fragment 1+2 [F1+2] and activated protein C-sensitivity ratio [APC-sr] and clot lysis time [CLT]). Data were analysed using logistic regression. Coagulation assays were performed in 353 individuals of whom 41 (12%) had a history of VTE; these belonged to 17 thrombophilic families. Of the tested variables only the ETP was associated with VTE (odds ratio [OR] 1.03 for each % increase, 95% confidence interval [CI] 1.01-1.05). However, the relatively low number of cases does not firmly exclude the other assays as candidate intermediate phenotypes for venous thrombosis. We found that an increased ETP may serve as an intermediate phenotype for VTE and may be used to discover novel inherited risk factors by genetic linkage analysis.
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PMID:Assessment of coagulation and fibrinolysis in families with unexplained thrombophilia. 1927 6

Activation of coagulation is an important hallmark of sickle cell disease (SCD) and it is believed that hypercoagulability plays a role to the disease pathophysiology. Studies have sought to identify how hemostatic biomarkers are expressed in SCD, however, the results are inconclusive. In this context, our objective was to evaluate the thrombin generation in vivo and ex vivo in SCD patients and the association between these biomarkers and the use of HU. This cross-sectional study was carried out with patients diagnosed with SCD, users or not of Hydroxyurea (HU), and healthy individuals as controls. D dimer (D-Di) was evaluated by ELISA and (TGT) thrombin generation test by CAT method. D-Di plasma levels were significantly higher in SCD patients when compared to the controls. TGT parameters such as peak, ETP and normalized ETP at low TF concentration and time-to-peak, peak, ETP and normalized ETP values at high TF concentration were lower in SCD patients than in controls. In contrast, the normalized activated protein C sensitivity ratio (nAPCsr) was higher in patients compared to controls, indicating resistance to the action of this natural anticoagulant. Regarding the use of HU, comparing users and non-users of this drug, no difference was observed in D-Di levels and in most TGT parameters. Our data analyzed together allow us to conclude that patients with SCD present a state of hypercoagulability in vivo due to the higher levels of D-Di and resistance to APC assessed ex vivo which is consistent with the coagulation imbalance described in SCD patients.
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PMID:Thrombin generation in vivo and ex vivo in sickle cell disease patients. 3322 76