Other entities represented in this entry:
HGNC Approved Gene Symbol: PLG
SNOMEDCT: 95844003; ICD10CM: E88.02;
Cytogenetic location: 6q26 Genomic coordinates (GRCh38): 6:160,702,193-160,754,097 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q26 | Angioedema, hereditary, 4 | 619360 | Autosomal dominant | 3 |
| Dysplasminogenemia | 217090 | Autosomal recessive | 3 | |
| Plasminogen deficiency, type I | 217090 | Autosomal recessive | 3 |
The PLG gene encodes plasminogen (PLG), a circulating zymogen that is converted to the active enzyme plasmin by cleavage of the peptide bond between arg560 and val561, which is mediated by urokinase (PLAU; 191840) and tissue plasminogen activator (PLAT; 173370). The main function of plasmin is to dissolve fibrin (see, e.g., FGA, 134820) clots. Plasmin, like trypsin, belongs to the family of serine proteinases (Miyata et al., 1982; Forsgren et al., 1987). Besides its importance in the fibrinolytic system, PLG is implicated in multiple other biologic processes, including cell migration, degradation of the extracellular matrix, and tissue remodeling (summary by Dewald, 2018).
Forsgren et al. (1987) isolated a full-length cDNA corresponding to the PLG gene from a human liver cDNA library. The deduced 791-residue nonglycosylated protein has a calculated molecular mass of 88.4 kD. After conversion, active plasmin consists of a heavy (A) and light (B) chain that have molecular masses of 63.2 and 25.2 kD, respectively. The N terminus of plasminogen corresponds to the heavy chain and contains 5 tandem repeats called kringles, which may mediate fibrin binding. The proteolytic active center of plasmin is located within the C-terminal light chain.
McLean et al. (1987) found that the human apolipoprotein(a) gene (LPA; 152200) shows striking similarities to the human PLG gene. In addition, both genes are located on chromosome 6q27.
Degen et al. (1990) isolated cDNA for the mouse Plg gene.
Angiostatin
O'Reilly et al. (1994) isolated a novel angiogenesis inhibitor, termed 'angiostatin,' from the urine and plasma of mice with lung carcinoma. It was found to be a 38-kD internal fragment of mouse plasminogen that contains the first 4 kringle structures. The circulating protein mediated the suppression of remote tumor metastases in mice by inhibiting the growth of capillary endothelial cells. Human angiostatin had the same effect on mouse tumors. Cao et al. (1996) demonstrated that recombinant fragments of angiostatin had inhibitory activity on capillary endothelial cell proliferation in vitro.
Gately et al. (1996) showed that angiostatin is produced by the proteolytic cleavage of plasminogen by a serine protease produced by several human prostate carcinoma cell lines.
Microplasmin
Wu et al. (1987) described the preparation and purification of a fully functional human microplasmin derived from native plasmin. Microplasmin is formed from the autolytic cleavage of plasmin in an alkaline solution. Microplasmin consists mainly of the light chain of native human plasmin and has a molecular mass of approximately 29 kD.
Wu et al. (1987) determined that microplasmin consists of 2 polypeptides connected by disulfide bonds. One polypeptide is the 230-residue light chain of plasmin and the other is a 31-residue fragment from the C terminal portion of the heavy chain. The calculated molecular mass is 28.6 kD.
Petersen et al. (1990) reported that the human plasminogen gene spans about 52.5 kb of DNA and contains 19 exons. They concluded that there is at least one other plasminogen-related gene in the human genome in addition to LPA.
Kida et al. (1997) characterized the 5-prime flanking region of the human plasminogen gene and found 3 TATA boxes 550 to 600 bp upstream of the transcription initiation site, a TATA-like sequence (TGTAA) at position -16, and putative binding sites for several transcription factors. The 1.1-kb 5-prime flanking sequence directed basal liver-specific expression in HepG2 cells, and deletion analysis identified 2 negative elements in the PLG promoter.
Eiberg et al. (1984) found a lod score of 7.37 at theta = 0.12 in males for linkage of FUCA2 (136820) and PLG. By somatic cell hybridization, Murray et al. (1985) mapped the PLG gene to chromosome 6. Using DNA probes for in situ mapping, Swisshelm et al. (1985) localized the gene to 6q25-q27. Murray et al. (1987) mapped the PLG locus to 6q26-q27 by study of somatic cell hybrids and by in situ hybridization. By fluorescence in situ hybridization, Rao et al. (1994) mapped the gene to 6q26.
Magnaghi et al. (1995) illustrated the orientation and relative position of the LPA and PLG genes and the apo(a)-like and plasminogen-like genes. The PLG and LPA genes are transcribed in opposite directions.
Degen et al. (1990) localized the mouse Plg gene to chromosome 17. Segregation of 2 allelic forms in 3 sets of recombinant inbred strains allowed localization within the t-complex. The gene was found to be deleted in the semidominant deletion mutant 'hairpintail.'
Mapping History
Hobart (1978, 1979) identified a diallelic polymorphism of plasminogen with gene frequencies about 0.7 and 0.3. Recombinants were found with HLA, C3, C6 and ABO.
Bissbort et al. (1983) found no linkage between PLG and 35 other marker genes. Although for the PLG:GC (138200) linkage, positive lod scores (up to 1.52 at theta = 0.20) were found in females, negative lod scores in males suggested caution in acceptance of this linkage as true. GC is located on chromosome 4q. The results were based on 18 families. Several studies gave negative evidence on the possible chromosome 4 localization of the PLG locus or, at best, weakly positive evidence (Falk and Huss, 1985; Buetow et al., 1985; Marazita et al., 1985).
Fischer et al. (2000) identified plasminogen, a proprotease implicated in neuronal excitotoxicity, as a PrPsc (176640)-binding protein. Binding is abolished if the conformation of the PrPsc is disrupted by 6-molar urea or guanidine. The isolated lysine-binding site-1 of plasminogen (kringles I-III) retains this binding activity, and binding can be competed for with lysine. Plasminogen does not bind to PrPc; thus plasminogen represents the first endogenous factor discriminating between normal and pathologic prion protein. Fischer et al. (2000) suggested that this unexpected property may be exploited for diagnostic purposes.
Nguyen et al. (2007) stated that kringle-5 (K5) of plasminogen is an inhibitor of angiogenesis and found that it induces autophagy and apoptosis in endothelial cells. They showed that exposure of human cell lines to recombinant K5 resulted in upregulated beclin-1 (604378) levels within a few hours, and progressively increasing amounts of antiapoptotic BCL2 (151430) became complexed with beclin-1. Prolonged exposure to K5 ultimately led to apoptosis via mitochondrial membrane depolarization and caspase activation (see CASP1, 147678) in endothelial cells. Knockdown of beclin-1 by RNA interference decreased K5-induced autophagy, but accelerated K5-induced apoptosis.
By immunoprecipitation and immunoblot analyses, Kunert et al. (2007) found that factor H (CFH; 134370) and factor H-related protein-1 (CFHR1; 134371) bound to surface-expressed Pseudomonas aeruginosa elongation factor Tuf and also to recombinant Tuf. Factor H and plasminogen bound simultaneously to Tuf, and plasminogen was proteolytically activated. Plasma without factor H did not support P. aeruginosa survival, and survival increased in a factor H dose-dependent manner. Kunert et al. (2007) proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and possibly facilitating tissue invasion.
Data on gene frequencies of allelic variants of plasminogen were tabulated by Roychoudhury and Nei (1988).
Plasminogen Deficiency, Type I
In 2 unrelated Turkish girls with type I plasminogen deficiency (217090) manifest as ligneous conjunctivitis, Schuster et al. (1997) identified 2 different homozygous mutations in the PLG gene, respectively (173350.0004; 173350.0005).
In a Turkish child, born of consanguineous Turkish parents, with plasminogen deficiency manifest as ligneous conjunctivitis and occlusive hydrocephalus, Schott et al. (1998) identified a homozygous nonsense mutation in the PLG gene (E460X; 173350.0006).
In 2 sibs with plasminogen deficiency originally reported by Bateman et al. (1986), Schuster et al. (1999) identified compound heterozygosity for 2 mutations in the PLG gene (173350.0008; 173350.0009).
Tefs et al. (2006) identified compound heterozygous or homozygous mutations in the PLG gene in 31 of 50 patients with type I plasminogen deficiency. In 7 patients, only a heterozygous mutation could be detected. No mutations in the PLG gene were identified in 12 patients of Turkish origin, but 9 of these cases had a homozygous combination of 3 common PLG polymorphisms suggestive of a founder effect. The most common mutation was K19E (173350.0010), which was present in 17 (34%) of 50 patients. Functional expression studies of 9 different type I mutant PLG variants in COS-7 cells showed decreased plasmin antigen levels, increased instability and degradation of the mutant protein, and impaired cellular secretion.
Dysplasminogenemia and Autosomal Dominant Plasminogen Deficiency
Initial studies suggested that heterozygous changes in the PLG gene resulting in dysfunctional plasminogen with decreased activity ('dysplasminogenemia') may predispose to thrombotic events (Aoki et al., 1978; Dolan et al., 1988). However, further studies (Shigekiyo et al., 1992; Tait et al., 1996) suggested that heterozygotes do not experience excess thrombotic events.
Dysfunctional plasminogen variants were described by Wohl et al. (1982), Miyata et al. (1984), Kazama et al. (1981), and Soria et al. (1983). Although the plasminogen variant was associated with thrombosis in the proband in most cases, family members who were also found to be heterozygous did not experience thrombotic events.
Aoki et al. (1978) reported a Japanese man with recurrent thrombosis who had decreased plasminogen activity with normal levels of immunoreactive plasminogen. Miyata et al. (1982) found that this patient was heterozygous for the Tochigi plasminogen variant (173350.0001). Multiple other family members with the variant did not have thrombotic events. Hach-Wunderle et al. (1988) found moderate plasminogen deficiency in a 53-year-old woman who developed deep venous thrombosis of the left thigh and calf following an injury to the leg. A similar deficiency of plasminogen was found in the patient's mother and sister who had no thrombotic episodes. This patient was the only example of plasminogen deficiency among 435 German individuals with a history of thromboembolism. Dolan et al. (1988) reported 3 unrelated individuals with decreased plasminogen activity and antigen associated with thrombosis. Investigation of family members showed other relatives with low levels of plasminogen who were asymptomatic. In 1 woman, Dolan et al. (1988) observed that plasminogen levels rose to within normal limits during pregnancy and returned to low levels after delivery. In a total of 8 pregnancies, no thrombotic events occurred.
Shigekiyo et al. (1992) studied the frequency of thrombosis in 21 heterozygotes for plasminogen deficiency in 2 unrelated families. Only 3 of the 21 individuals had thromboses. Analysis by the Kaplan-Meier method suggested no difference in frequency of thrombotic events from controls.
Patrassi et al. (1993) reported a 17-year-old man with thrombotic-like retinopathy associated with heterozygous plasminogen deficiency. Five of 13 paternal relatives had the same decrease, 2 of whom had a history of recurrent phlebites of the legs. However, another family member with normal plasminogen also had superficial phlebites. No other family members showed retinal abnormality.
Magnaghi et al. (1995) reported a 37-year-old Italian man who developed a deep venous thrombosis and pulmonary embolism following a hip fracture in a car accident. He had decreased plasminogen activity and antigen (63% and 65%, respectively). Analysis of the family identified a haplotype associated with the abnormal plasminogen, which was inherited in an autosomal dominant pattern. A brother who carried the same haplotype had a lethal ischemic stroke at age 41 years. However, another family member without plasminogen deficiency died of posttraumatic pulmonary embolism at age 39, and there were multiple family members without thrombotic events who were heterozygous and even homozygous for the abnormal plasminogen haplotype.
Iijima et al. (1998) reported a 49-year-old woman with unilateral central retinal vein occlusion and ipsilateral cilioretinal artery occlusion who showed familial dysplasminogenemia associated with elevated lipoprotein(a). Decreased plasminogen activity without reduction of plasminogen antigen was found in the patient, her 2 sibs, and her 2 children.
Hereditary Angioedema 4
In 60 patients from 13 unrelated families of European descent with hereditary angioedema-4 (HAE4; 619360), Bork et al. (2018) identified a heterozygous missense mutation in exon 9 of the PLG gene (K330E; 173350.0011). The mutation, which was found by whole-exome sequencing or next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was some evidence of incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but 3 patients studied had normal plasminogen activity. The authors postulated a founder effect.
In 18 patients from 3 unrelated multigenerational German families with HAE4, Dewald (2018) identified heterozygosity for the K330E mutation in the PLG gene. Isoelectric focusing of patient plasma identified aberrant PLG protein bands that were different from controls. The findings suggested that the mutation caused some quantitative and qualitative effects on the glycosylation of plasminogen, which the authors termed 'dysplasminogenemia.' The K330E substitution is located in the kringle 3 domain important for binding that enables plasminogen or plasmin to interact with other protein ligands. This residue is conserved in humans but is a glutamic acid residue in all other species examined, suggesting that the mutation actually reverses the evolution of the human K3 sequence and corresponds to the reappearance of the ancestral amino acid state. Functional studies of the variant and studies of patient cells were not performed, but Dewald (2018) speculated that the mutation could affect the affinity of binding partners and thus have functional consequences, particularly on the kinin pathway that regulates circulating vasoactive substances. Dewald (2018) noted that a c.1100A-G transition (NM_0003013.3), resulting in a lys311-to-glu (K311E) substitution of the mature PLG protein, corresponds to c.988A-G (K300E) if nucleotide numbering starts with the A of the ATG translation initiation codon.
Yakushiji et al. (2018) identified heterozygosity for the K330E mutation in 4 affected patients from 2 unrelated Japanese families. Functional studies of the variant were not performed, but the report confirmed that this mutation can be found in various ethnic populations. The mutations were found by direct sequencing of exon 9 of the PLG gene in 20 unrelated Japanese probands with HAE and normal C1INH levels.
Belbezier et al. (2018) identified the K330E mutation in 10 patients from 3 unrelated French families with HAE4. Functional studies of the variant and studies of patient cells were not performed. The patients were part of a cohort of 15 families who underwent genetic testing, thus accounting for 20%.
Farkas et al. (2021) reported a 60-year-old woman (patient E385) with HAE and the K330E mutation. The patient was identified from 124 patients with HAE of unknown origin whose cells were in a repository and were tested retrospectively. Her son, who also carried the common K330E mutation in the PLG gene, was asymptomatic. Functional studies of the variant were not performed, but the authors speculated that this variant in the PLG gene results in enhanced activation of the fibrinolytic system, with the generation of plasmin, activation of the kinin-kallikrein system, and bradykinin release.
In a 52-year-old Greek man and his 15-year-old son with HAE4, Loules et al. (2020) identified a heterozygous missense mutation in the PLG gene (V728E; 173350.0012). The mutation, which was found through a targeted gene panel, segregated with the disorder in the family. The man's 10-year-old asymptomatic daughter also carried the variant, suggesting incomplete penetrance. Functional studies of the variant and studies of patients cells were not performed, but the variant was predicted to affect the plasminogen/plasmin system and the kinin pathway, leading to altered vascular permeability. Clinical details were limited, but the patients had normal C1INH levels.
Bugge et al. (1995) reported that Plg-deficient mice completed embryonic development, survived to adulthood, and were capable of reproduction. However, the mice developed multiple spontaneous thrombotic lesions leading to severe organ damage and high morbidity or mortality at an early age. Urine levels of urokinase-type plasminogen activator were normal.
Ploplis et al. (1995) found that Plg-null mice developed spontaneous fibrin deposition due to impaired thrombolysis and exhibited retarded growth and reduced fertility and survival compared to wildtype mice.
Romer et al. (1996) analyzed skin wound repair in Plg knockout mice and demonstrated that Plg is required for normal repair of skin wounds.
Drew et al. (1998) and Kao et al. (1998) found that mice with targeted disruption of the plasminogen gene developed ligneous conjunctivitis characterized by the formation of the fibrin-rich viscous or membranous material.
A number of studies have shown that gram-negative and gram-positive bacteria can interact with the host plasminogen activation system to increase their invasiveness and enhance their ability to cross tissue barriers (Boyle and Lottenberg, 1997). Gebbia et al. (1999) studied the role of the plasminogen activation system during the course of infection of relapsing fever caused by a species of Borrelia in plasminogen knockout mice (Plg -/-). Subcutaneous inoculation of spirochetes achieved a similar peak spirochetemia in control and deficient mice, indicating that the plasminogen activation system had no effect on the development of this phase of the infection. Anemia, thrombocytopenia, hepatitis, carditis, and splenomegaly were noted in all mice during and immediately after peak spirochetemia. Fibrin deposition in organs was noted in Plg -/- mice but not in controls. Significantly greater spirochetal DNA burdens were consistently observed in the hearts and brains of control mice 28 to 30 days after infection. Furthermore, the decreased spirochetal load in brains of Plg -/- mice was associated with a significant decrease in the degree of inflammation of the leptomeninges in these mice. These findings indicated a role for the plasminogen activation system in heart and brain invasion by relapsing fever Borrelia, resulting in organ injury.
Swaisgood et al. (2002) evaluated the in vivo effect of plasma carboxypeptidase B (CPB2; 603101) on plasminogen function. Cpb2-deficient mice, generated by homologous recombination, were healthy and did not exhibit the poor health characteristics of Plg-deficient mice. In a pulmonary clot lysis model, fibrinolysis was significantly increased in mice with partial (Cpb2 +/-) or total (Cpb2 -/-) absence of Cpb2 compared with their wildtype counterparts (Cpb2 +/+). In a thioglycollate model of peritoneal inflammation, leukocyte migration at 72 hours increased significantly in Plg +/-/Cpb2 +/- and Plg +/-/Cpb2 -/- compared with their wildtype counterparts. The studies demonstrated that Cpb2 regulates primary functions of Plg in fibrinolysis and cell migration in vivo.
Gong et al. (2008) found that Plg -/- mice displayed diminished macrophage trans-extracellular matrix (ECM) migration and decreased Mmp9 (120361) activation following induction of peritonitis. Injection of active Mmp9 rescued macrophage migration in Plg -/- mice. Macrophage migration and aneurysm formation were also reduced in Plg -/- mice induced to undergo abdominal aortic aneurysm (AAA). Administration of active Mmp9 to Plg -/- mice promoted macrophage infiltration and development of AAA. Gong et al. (2008) concluded that PLG regulates macrophage migration in inflammation via activation of MMP9, which in turn regulates the ability of macrophages to migrate across ECM.
Angiostatin
Cao et al. (1998) demonstrated that gene transfer of a cDNA coding for mouse angiostatin into murine T241 fibrosarcoma cells suppressed primary and metastatic tumor growth in vivo. Implementation of stable clones expressing mouse angiostatin in C57B16/J mice inhibited primary tumor growth by an average of 77%. After removal of primary tumors, the pulmonary micrometastases in approximately 70% of mice remained in a microscopic dormant and avascular state for 2 to 5 months. The tumor cells in the dormant micrometastases exhibited a high rate of apoptosis balanced by a high proliferation rate. These studies showed the diminished growth of lung metastases after removal of the primary tumor, suggesting that metastases are self-inhibitory by halting angiogenesis. The angiostatin-induced long-term dormancy of lung metastases was equivalent to 14 to 15 human years (when 1 mouse day is equivalent to approximately 35 human days).
Drixler et al. (2001) examined the biologic effects of angiostatin on pathologic and physiologic retinal angiogenesis as well as its effects on growth and development in newborn mice. They found that angiostatin successfully inhibited oxygen-induced intravitreal pathologic angiogenesis without affecting the development of physiologic retinal vascularization, development, and growth.
Lund et al. (2006) observed that wound healing in Plat-null or Plau-null mice was similar to that in wildtype mice, but wound healing in mice deficient for both Plat and Plau was significantly delayed. These findings suggested functional overlap between the 2 plasminogen activators. However, wound healing in the Plat/Plau-deficient mice was not as impaired as in plasminogen-null mice, suggesting the presence of an additional plasminogen activator. Pharmacologic inhibition of kallikrein (KLK1; 147910) in Plat/Plau-null mice resulted in delayed wound healing similar that in Plg-null mice. Lund et al. (2006) concluded that kallikrein may play a role in plasmin generation.
Miyata et al. (1982) identified a variant of plasminogen with an ALA600THR (A600T) substitution, caused by a G-to-A transition in exon 15 of the PLG gene, in the active site of the enzyme. (Ala600 is the equivalent of ala55 in the chymotrypsin numbering system.) The authors referred to this variant as plasminogen Tochigi. The A600T substitution was identified in a 31-year-old Japanese man with a 15-year history of recurrent thromboses originally reported by Aoki et al. (1978). Serum plasminogen activity was decreased by about 50%, but plasminogen antigen levels were normal; see 217090. Detailed family studies reported by Aoki et al. (1978) identified 12 additional members with half-normal plasminogen activity, presumably heterozygotes, and 1 young girl with no plasminogen activity, presumably a homozygote. None of the family members had thrombotic episodes. Gel electrofocusing of the purified plasminogen confirmed the abnormality in this family. Aoki et al. (1978) noted that the low level of plasminogen activity in this patient could not be the sole cause of thrombosis because none of the other affected family members had a thrombotic event. Miyata et al. (1982) suggested that the A600T substitution may perturb the protein such that proton transfers associated with the normal catalytic process cannot occur in the abnormal enzyme. Miyata et al. (1984) found that plasminogen Tochigi II and Nagoya, both of which showed decreased enzyme activity, were also due to the A600T substitution.
Ichinose et al. (1991) described the same variation, which they referred to as ala601-to-thr.
By isoelectric focusing electrophoresis, several workers identified a functionally inactive PLG variant designated plasminogen M5, present in 2 to 4% of Japanese subjects (review by Kikuchi et al., 1992). Kikuchi et al. (1992) demonstrated that plasminogen Tochigi and plasminogen Nagoya II are identical to PLG M5. The plasma levels of immunoreactive plasminogen associated with the A601T substitution are normal, but activity is reduced. Despite the report of Aoki et al. (1978), the role of the A601T substitution in thrombotic events was unclear; many heterozygous and even homozygous individuals did not have a history of thrombosis. Kikuchi et al. (1992) estimated the allele frequency to be 0.011 to 0.023 in the Japanese population.
Murata et al. (1997) studied 3 patients with retinochoroidal vascular disorders and found that each carried the A601T mutation. They suggested that this defect may play a role in the pathogenesis of circulatory disorders in small local vessels because of reduced fibrinolytic activity due to decreased functional plasminogen levels.
This variant has also been called plasminogen Kagoshima.
Ichinose et al. (1991) described a G-to-T transversion in exon 10 of the PLG gene, resulting in a val355-to-phe (V355F) substitution just prior to the first disulfide bond in kringle 4. The V355F substitution was associated with decreased plasminogen activity and antigen levels (see 217090). This mutation was demonstrated by digestion with AvaII endonuclease, which recognized the normal GGTCC but not GTTCC.
This variant has been called plasminogen Nagoya I.
In a 43-year-old Japanese woman with late-onset epilepsy as a result of cerebral infarction, Azuma et al. (1993) identified a heterozygous T-to-C transition in exon 14 of the PLG gene, resulting in a ser572-to-pro (S572P) substitution. Biochemical analysis showed decreased PLG antigen levels and activity to about 50% of normal, consistent with dysplasminogenemia (see 217090). The patient's mother and daughter, who both carried the mutation, had similarly decreased PLG antigen and activity. The mother had an episode of arterial thrombosis of the femur at age 56 years.
In a Turkish girl with severe plasminogen deficiency (217090) manifest as ligneous conjunctivitis and occlusive hydrocephalus, Schuster et al. (1997) identified a homozygous 780G-A transition in exon 7 of the PLG gene, resulting in an arg216-to-his (R216H) substitution. The mutation was identified using PCR, SSCP analysis, and DNA sequencing. The patient's unaffected parents and sister were heterozygous for the mutation.
In a previously healthy 71-year-old woman who had first developed unilateral ligneous conjunctivitis at the age of 69 years, Schuster et al. (1999) identified compound heterozygosity for 2 mutations in the PLG gene: R216H and K19E (173350.0010).
In a Turkish girl with severe plasminogen deficiency (217090) manifest as ligneous conjunctivitis and occlusive hydrocephalus, Schuster et al. (1997) identified a homozygous 1924G-A transition in exon 15 of the PLG gene, resulting in a trp597-to-ter (W597X) substitution. The healthy parents were heterozygous for the mutation.
In a child of a consanguineous Turkish couple with plasminogen deficiency (217090) manifest as ligneous conjunctivitis and occlusive hydrocephalus, Schott et al. (1998) identified a homozygous 1511G-T transversion, resulting in a glu460-to-ter (E460X) substitution. The mutation abolished the catalytic domain of plasmin. A healthy brother and the unaffected parents were heterozygous for the mutation.
Higuchi et al. (1998) identified a new dysplasminogen, plasminogen Kanagawa-I, in a healthy 20-year-old male with no past history of thrombosis or bleeding. He was found to have dysplasminogenemia (see 217090) following voluntary blood donation for teaching purposes. His plasma plasminogen activity was approximately 50% of that of normal pooled plasma. Nucleotide sequencing revealed a heterozygous G-to-A transition in exon 18, which resulted in a gly732-to-arg (G732R) substitution. Both the proband's father and paternal grandfather were heterozygous for this mutation. The grandfather was a compound heterozygote for plasminogen Kanagawa-I and Tochigi (173350.0001); his plasminogen activity and antigen levels were 7.7% and 87.2% of that of normal pooled plasma, respectively. He had never had significant thrombosis.
In a brother and sister with plasminogen deficiency (217090), Schuster et al. (1999) identified compound heterozygosity for 2 mutations in the PLG gene: a deletion of lys212 inherited from the mother, and a 1-bp deletion in the first nucleotide of intron Q following exon 17 (173350.0009) inherited from the father. Both sibs had plasminogen antigen and functional activity levels below the limit of detection. The sibs were originally reported by Bateman et al. (1986).
For discussion of the 1-bp deletion in the first nucleotide of intron Q following exon 17 in the PLG gene that was found in compound heterozygous state in a brother and sister with plasminogen deficiency (217090) by Schuster et al. (1999), see 173350.0008.
In 3 unrelated individuals with plasminogen deficiency (217090), Schuster et al. (1999) identified a 118A-G transition in exon 2 of the PLG gene resulting in a lys19-to-glu (K19E) substitution. All patients were compound heterozygous for K19E and another pathogenic PLG mutation (see, e.g., 173350.0004).
Schuster and Seregard (2003) stated that the K19E mutation was the most common PLG mutation identified in patients with plasminogen deficiency.
Tefs et al. (2006) identified the K19E mutation in 17 (34%) of 50 patients with plasminogen deficiency. Six patients who were homozygous for the mutation had a milder clinical course and higher residual PLG antigen and activity compared to patients with other PLG mutations.
Note: A c.1100A-G transtion (NM_0003013.3), resulting in a lys311-to-glu (K311E) substitution of the mature protein, corresponds to c.988A-G (K300E) if nucleotide numbering starts with the A of the ATG translation initiation codon (Dewald, 2018).
In 60 patients from 13 unrelated families of European descent with hereditary angioedema-4 (HAE4; 619360), Bork et al. (2018) identified a heterozygous c.988A-G transition (c.988A-G, NM_000301) in exon 9 of the PLG gene, resulting in a lys330-to-glu (K330E) substitution at a conserved residue in the kringle 3 domain. The mutation, which was found by whole-exome sequencing or next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was some evidence for incomplete penetrance. This numbering is based on the primary translation product. This variant was not present in the dbSNP, ExAC, or 1000 Genomes Project databases; it was found once in gnomAD (1 in 31,591 alleles in the European population). Functional studies of the variant and studies of patient cells were not performed, but 3 patients studied had normal plasminogen activity. The authors postulated a founder effect.
In 18 patients from 3 unrelated multigenerational German families with HAE4, Dewald (2018) identified the heterozygous K330E mutation in the PLG gene. The authors stated that this was a c.1100A-G transition, resulting in a lys311-to-glu (K311E) substitution in the mature protein. Isoelectric focusing of patient plasma identified aberrant PLG protein bands that were different from controls. The findings suggested that the mutation caused some quantitative and qualitative effects on the glycosylation of plasminogen. The K330E substitution is located in the kringle 3 domain important for binding that enables plasminogen or plasmin to interact with other protein ligands. This residue is conserved in humans, but is a glutamic acid residue in all other species examined, suggesting that the mutation actually reverses the evolution of the human K3 sequence and corresponds to the reappearance of the ancestral amino acid state. Functional studies of the variant and studies of patient cells were not performed, but Dewald (2018) speculated that the mutation could affect the affinity of binding partners and thus have functional consequences, particularly on the kinin pathway that regulates circulating vasoactive substances.
Yakushiji et al. (2018) identified a heterozygous K330E mutation in 4 affected patients from 2 unrelated Japanese families. Functional studies of the variant were not performed, but the report confirmed that this mutation can be found in various ethnic populations. The mutations were found by direct sequencing of exon 9 of the PLG gene in 20 unrelated Japanese probands with HAE and normal C1INH levels.
Belbezier et al. (2018) identified the K330E mutation in 10 patients from 3 unrelated French families with HAE4. Functional studies of the variant and studies of patient cells were not performed. The patients were part of a cohort of 15 families who underwent genetic testing, thus accounting for 20%.
Farkas et al. (2021) reported a 60-year-old woman (patient E385) with HAE and the K330E mutation. The patient was identified from 124 patients with HAE of unknown origin whose cells were in a repository and were tested retrospectively. Her son, who also carried the common K330E mutation in the PLG gene, was asymptomatic. Functional studies of the variant were not performed, but the authors speculated that this variant in the PLG gene results in enhanced activation of the fibrinolytic system, with the generation of plasmin, activation of the kinin-kallikrein system, and bradykinin release.
Dickeson et al. (2022) purified wildtype PLG and mutant PLG with the K311E mutation following expression in Expi293 cells. When tPA was added to normal plasma that was supplemented with either wildtype or K311E PLG, bradykinin (BK) generation was significantly higher with K311E. This increased generation of BK was not dependent on prekallikrein or factor XII (F12; 610619). K311E was also shown to liberate BK from both high and low molecular weight kininogens (HK and LK) faster than wildtype. Dickeson et al. (2022) concluded that K311E contributes to angioedema by directly catalyzing kinin release from HK and LK.
In a 52-year-old Greek man and his 15-year-old son with hereditary angioedema-4 (HAE4; 619360), Loules et al. (2020) identified a heterozygous c.2183T-A transversion in the PLG gene, resulting in a val728-to-glu (V728E) substitution in the serine protease domain. The mutation, which was found through a targeted gene panel, segregated with the disorder in the family. The man's 10-year-old asymptomatic daughter also carried the variant, suggesting incomplete penetrance. Functional studies of the variant and studies of patients cells were not performed, but the variant was predicted to affect the plasminogen/plasmin system and the kinin pathway, leading to altered vascular permeability. Clinical details were limited, but the patients had normal C1INH levels.
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