Molecular Pathogenesis
PAI-1, a protein that is a member of the serine protease inhibitor (SERPIN) superfamily, is involved in a variety of pathophysiologic systems including embryogenesis, angiogenesis, ovulation, inflammation, and tumor metastasis. These observations suggest that the plasminogen activation system is an important mediator of tissue remodeling and cell migration [Gupta et al 2014] (full text).
In hemostasis, PAI regulates fibrinolysis (i.e., the degradation of thrombi) [Gupta et al 2014]. PAI-1 is an inhibitor of tissue type plasminogen activators (t-PA) and urokinase type plasminogen activators (u-PA), which convert plasminogen to plasmin, the primary protease responsible for fibrinolysis. Thus, complete PAI-1 deficiency results in excessive fibrinolysis manifesting as mild-to-moderate bleeding [Heiman et al 2014]. Physiologic fibrinolysis occurs exclusively on the clot surface within a blood vessel and not in the circulation [Gupta et al 2014] (see ).
Plasminogen activators – urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) – circulate in plasma as a reversible complex with PAI-1. When the fibrin clot is formed, plasminogen and t-PA or u-PA bind to the (more...)
Heterozygous pathogenic variants in SERPINE1 may be associated with qualitative PAI-1 deficiency (i.e., normal PAI-1 antigen levels and decreased PAI-1 activity), the clinical significance of which is unknown. Thus, the significance of reports of families with qualitative PAI-1 deficiency and a heterozygous SERPINE1 variant should be interpreted with caution because (1) the PAI-1 activity assays used in these families lack the sensitivity to differentiate between low normal activity and complete deficiency, and (2) the SERPINE1 variants identified are of uncertain clinical significance (i.e., some variants reported as pathogenic may actually be benign).
Although beyond the scope of diagnostic laboratories, studies to determine the functional consequences of a SERPINE1 variant may be of value in these circumstances. Of note, in vitro expression analyses demonstrated that the c.699_700dupTA variant of the Old Order Amish community resulted in the synthesis of an insoluble, unstable protein [Fay et al 1992]. However, currently there are no clinically useful functional PAI-1 assays. Note: A fibrinolysis assay with a euglobulin clot lysis time is not sensitive or specific to PAI-1.
Gene structure.
SERPINE1 spans approximately 12 kb and comprises nine exons. A variety of regulatory elements have been identified in SERPINE1, including AP-1 sites, a glucocorticoid response element, a VLDL response site, and two Sp1 sites that appear to mediate glucose responsiveness. See Table A, Gene for a detailed summary of gene and protein information.
Modulator. The SERPINE1 c.-820_-817G(4_5) (commonly known as 4G/5G) benign variant is a common insertion/deletion of four or five G-nucleotide residues in the SERPINE1 promoter region; the 4G allele is associated with higher plasma PAI-1 activity. An elevation in plasma PAI-1 activity leads to depressed fibrinolytic activity and a theoretically increased risk for arterial and venous thrombosis, a significant risk factor for coronary artery disease, myocardial infarction, and recurrent miscarriage [Huang et al 2017]. This benign variant is mentioned only to point out that testing for the 4G/5G variant will not aid in diagnosing an individual with complete PAI-1 deficiency.
Pathogenic variants. The first individual reported to have a bleeding disorder resulting from biallelic SERPINE1 pathogenic variants was a child from the Old Order Amish community of eastern and southern Indiana who was homozygous for a dinucleotide insertion in exon 4 (c.699_700dupTA), resulting in a frameshift leading to a premature stop codon [Fay et al 1992]. Subsequently in this Old Order Amish community: (1) eleven additional individuals with a bleeding disorder have been determined to be homozygous for this pathogenic variant, and (2) 96 individuals heterozygous for this pathogenic variant – none of whom experienced bleeding – have been identified [Indiana Hemophilia and Thrombosis Center, unpublished data].
Since 1992 two additional SERPINE1 pathogenic variants associated with a bleeding disorder have been reported:
c.356dupC. A woman age 47 years with a lifelong history of major bleeding (including extreme menorrhagia and post-surgical and postpartum bleeding) and impaired wound healing had an undetectable PAI-1 antigen level. She was
homozygous for a 1-bp
duplication leading to a frameshift and a premature stop codon [
Iwaki et al 2011].
Table 3.
SERPINE1 Variants Discussed in This GeneReview
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Variant Classification | DNA Nucleotide Change (Alias 1) | Predicted Protein Change 2 | Reference Sequences |
---|
Modulator
| c.-820_-817G(4_5) 3 (4G/5G) | -- |
NM_000602.4
NP_000593.1
|
Pathogenic
| c.43G>A | p.Ala15Thr |
c.356dupC | p.Ile120AspfsTer42 |
c.699_700dupTA | p.Thr234IlefsTer45 |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
- 2.
Numbering relative to full-length protein
- 3.
Not associated with the complete PAI-1 deficiency phenotype but can affect measured PAI-1 activity levels. A 1-bp guanine deletion/insertion variant in promoter (rs587776796) associated with higher transcription and activity levels and other phenotypes, including coronary artery disease (see OMIM 173360).
Normal gene product. The full-length gene product, PAI-1, is a 47-kd protein of 402 amino acids in length including the 23-residue signal peptide. The active mature form of PAI-1 in plasma is 379 amino acids in length.
The key functional domains of the full-length protein are:
The Arg-Met reactive site at residues 369-370;
A vitronectin binding site;
Glycosylation sites at residues 232, 288, and 352.
Abnormal gene product. PAI-1 deficiency may result from either complete plasma protein deficiency (absence of PAI-1 activity and antigen) as in the kindred described above or a dysproteinemic state with presence of the antigen but absence of activity.
The loss-of-function pathogenic variant c.699-700 dup TA resides in exon 4 of the coding sequence at amino acid 210, resulting in a frameshift and formation of a premature stop codon and the synthesis of a truncated, non-functional PAI-1 protein.
The c.43G>A variant in the signal peptide may partly impair secretion of PAI-1 [Zhang et al 2005].