The relationship between PLG and Hypoplasminogenemia (Dysplasminogenemia and Plasminogen deficiency, type I, included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of September, 2019. PLG was reported in relation to Hypoplasminogenemia as early as 1997 (Schuster et al, 1997, PMID: 9242524; Murata, 1997, PMID: 9375744). At least 11 unique variants including nonsense, splice site, frameshift and missense have been reported in humans. PLG encodes plasminogen, which is secreted as a zymogen and is activated by proteolysis and converted to plasmin and angiostatin. Plasmin is involved in fibrinolysis. Hypoplasminogenemia or congenital plasminogen deficiency is characterized by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature (PMID: 12850227). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (12 Points): Variants in this gene have been reported in at least 10 probands in 7 publications (PMID: 9834305, 9242524, 10233898, 9375744, 16849641, 9255907, 11477736). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.
The mechanism for disease is expected to be biallelic loss of function.
Summary of Experimental Data (4.5 points): This gene-disease association is supported by mouse models and in vitro functional assays. The PLG knock-out mouse generated by Bugge et al, (PMID: 7705657) has been shown to recapitulate ligneous conjunctivitis (PMID: 9473227). Plasminogen is involved in fibrinolysis, and the loss of the activity due to PLG variants results in abnormal fibrin deposition in tissues, as observed in individuals with plasminogen deficiency (PMID: 9501859). Plasminogen is largely synthesized in the liver, with expression limited to liver and kidney; however, plasminogen is also shown to be synthesized by the corneal epithelium (PMID: 10215610). Therapeutic administration of Glu-Plasminogen is shown to improve symptoms in individuals with PLG variants and plasminogen deficiency (PMID: 29321155).
In summary, PLG is definitively associated with Autosomal Recessive Hypoplasminogenemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on October, 23, 2019 (SOP Version 7).
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