CoagMDB: a database analysis of missense mutations within four conserved domains in five vitamin K-dependent coagulation serine proteases using a text-mining tool

Abstract

Communicated by John McVeyCentral repositories of mutations that combine structural, sequence, and phenotypic information in related proteins will facilitate the diagnosis and molecular understanding of diseases associated with them. Coagulation involves the sequential activation of serine proteases and regulators in order to yield stable blood clots while maintaining hemostasis. Five coagulation serine proteases-factor VII (F7), factor IX (F9), factor X (F10), protein C (PROC), and thrombin (F2)-exhibit high sequence similarities and all require vitamin K. All five of these were incorporated into an interactive database of mutations named CoagMDB (http://www.coagMDB.org; last accessed: 9 August 2007). The large number of mutations involved (especially for factor IX) and the increasing problem of out-of-date databases required the development of new database management tools. A text mining tool automatically scans full-length references to identify and extract mutations. High recall rates between 96 and 99% and precision rates of 87 to 93% were achieved. Text mining significantly reduces the time and expertise required to maintain the databases and offers a solution to the problem of locus-specific database management and upkeep. A total of 875 mutations were extracted from 1,279 literature sources. Of these, 116 correspond to Gla domains, 86 to the N-terminal EGF domain, 73 to the C-terminal EGF domain, and 477 to the serine protease domain. The combination of text mining and consensus domain structures enables mutations to be correlated with experimentally-measurable phenotypes based on either low protein levels (Type I) or reduced functional activities (Type II), respectively. A tendency for the conservation of phenotype with structural location was identified. Hum Mutat 29(3), [333][334][335][336][337][338][339][340][341][342][343][344] 2008.

In Silico profiling of deleterious amino acid substitutions of potential pathological importance in haemophlia A and haemophlia B

“…In vivo and in vitro studies on the function of nsSNPs have found that genetic mutations in F8 and F9 gene are responsible for Haemohpilia A and Haemohpilia B. There have been a quite lot of studies existing to validate the importance of single amino acid substitutions in Haemophlia A and Haemophilia B at activation cleavage sites [65,133,134], affecting factor VIII binding to von Willebrand factor [65,101,135] factor VIII secretion [92] and factor IX binding to factor VIII [136-138]. Recently Markoff by his homology modeling approach analyzed the impact of substitutions in loss of S-S bridges, thrombin activation site, gain/loss of H-bonds, cross-chain H-bonds, ionic bond and possible contact residue in FVIII [132].…”

“…Recently Markoff by his homology modeling approach analyzed the impact of substitutions in loss of S-S bridges, thrombin activation site, gain/loss of H-bonds, cross-chain H-bonds, ionic bond and possible contact residue in FVIII [132]. The information regarding the involvement of mutations in Gla (g-carboxyglutamic acid) domain, EGF1 for the N-terminal domain that binds calcium, EGF2 where it does not bind calcium, and a catalytic serine protease (SP) domain has been deposited in CoagMDB database [138]. The most commonly observed amino acid substitutions are Arg, Tyr, Phe and Cys in FVIII and FIX which play important role in altering the protein function.…”

Protein C anticoagulant and cytoprotective pathways

“…Infants with severe deficiency present with massive thrombotic complications, and if they survive due to maintenance replacement therapy, they tend to present with mental retardation and/or visual impairment [82, 83]. Hundreds of mutations of protein C in thrombosis patients have been reported (see protein C mutation databases [84, 85]) and the basis for hereditary protein C defects can most often be rationalized based on the structure of protein C [86, 87]. Acquired protein C deficiency arises during initiation of Coumadin therapy due to the relatively short half life of protein C (T ½ ~ 8 h) compared to most procoagulant vitamin K-dependent factors (T ½ ~ 20 to 48 h), leading to the conventional wisdom of using heparin during initiation of therapy.…”

ABCMdb: A database for the comparative analysis of protein mutations in ABC transporters, and a potential framework for a general application

“…Biomedical text mining is a large field with a wide range of applications such as the automatized extraction of protein–protein interactions [Krallinger et al, 2011], protein mutations [Caporaso et al, 2007; Doughty et al, 2011; Lee et al, 2007; Rebholz‐Schuhmann et al, 2004], pharmacokinetic relationships between genes, drugs, and diseases [Frijters et al, 2010; Garten et al, 2010; Rubin et al, 2005] or protein and gene annotation [Camon et al, 2005]. Several methods have been implemented and applied successfully to mine human kinase mutations [Krallinger et al, 2009], mutations of G‐protein coupled receptors (GPCRs), nuclear hormone receptors (NRs) [Horn et al, 2004], vitamin K‐dependent coagulation serine proteases [Saunders and Perkins, 2008], and α‐galactosidase A mutations related to Fabry disease [Kuipers et al, 2010]. A database that aims to gather protein level enzyme mutations having an effect on protein stability or function from PubMed abstracts is also available [Yeniterzi and Sezerman, 2009].…”