title: Val17Ile single nucleotide polymorphisms similarly as Ala15Thr could be related to the lower secretory dynamics of PAI-1 secretion: theoretical evidence.
abstract: Plasminogen activator inhibitor (PAI-1) is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). In that way PAI-1 regulates proteolytic activity of many physiological and pathological processes [1-3]. PAI-1 plays an important role in blood coagulation controlling clot lysis which is triggered by tPA activated plasminogen [4]. Only two types of mutations are reported to be associated with PAI-1; one is the frame-shift mutation in exon 4 of PAI-1 gene resulting in a truncated nonfunctional protein and in complete PAI-1 deficiency. The other SNP causes Ala15Thr mutation in the signal peptide. A literature search revealed five variants of polymorphisms during a study of over one thousand individuals. Two are associated with thrombophilia (765 4G/5G and -844 A>G, in the promoter), risk of myocardial infarction and postoperative deep venous thrombosis related to higher than normal levels of PAI-1. The other SNPs associated with PAI-1 deficiency are Ala15Thr, Val17Ile and they are located in the central hydrophobic core of the PAI-1 signal peptide of PAI-1 and Asn195Ile in the 'A' β sheet of the PAI-1. We have analyzed two SNPs not reported to be associated with PAI-1 deficiency. Our analysis suggests that Val17Ile PAI-1 variant might cause slower PAI-1 secretion leading to the deficiency at time and place where it is needed in a similar way as for Ala15Thr SNP. The Asn195Ile mutant may be more stable only as latent form thus no PAI-1 deficiency is expected in this mutant.
authors.affiliation: Urology Research Center, Department of Urology, The University of Toledo - Health Science Campus, OH 43614, USA. jerzy.jankun@utoledo.edu
authors.forename: J
authors.initials: J
authors.lastname: Jankun
authors.forename: E
authors.initials: E
authors.lastname: Skrzypczak-Jankun
mesh_terms: D020022:Genetic Predisposition to Disease; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D019851:Thrombophilia / Q000235:genetics; D020246:Venous Thrombosis / Q000235:genetics
chemical_list: D017395:Plasminogen Activator Inhibitor 1