Val17Ile Single Nucleotide Polymorphisms Similarly as Ala15Thr Could be Related to the Lower Secretory Dynamics of PAI-1 Secretion – Theoretical Evidence

Author(s): J. Jankun, E. Skrzypczak-Jankun.

Journal Name: Current Molecular Medicine

Volume 11 , Issue 6 , 2011

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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.

Keywords: PAI-1 deficiency, SNP, Val17Ile, Ala15Thr, urokinase plasminogen, proteolytic activity, clot lysis, activated plasminogen, promoter, exon, translocation, amino acid, Euglobulin clot lysis, platelet, mutation

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Article Details

VOLUME: 11
ISSUE: 6
Year: 2011
Page: [512 - 516]
Pages: 5
DOI: 10.2174/156652411796268678
Price: $58

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