PLG – Hypoplasminogenemia

PLG encodes plasminogen, the zymogen of the fibrinolytic protease plasmin. Biallelic loss-of-function variants in PLG cause type I congenital plasminogen deficiency, clinically manifesting as hypoplasminogenemia with ligneous conjunctivitis and other mucosal fibrin pseudomembranes. The inheritance is autosomal recessive, with heterozygous carriers typically asymptomatic or exhibiting mild reductions in plasminogen activity. There is no known gain-of-function or dominant-negative mechanism; pathogenicity arises from reduced plasminogen secretion and activity.

Genetic evidence includes three unrelated patients with severe hypoplasminogenemia harboring distinct PLG mutations identified by isoelectric focusing and sequence analysis of 24 healthy subjects and six patients with inherited deficiencies (n=3 patients) (PMID:15269832). All affected individuals carried compound heterozygous or homozygous missense and splice-site variants leading to absent or markedly reduced plasminogen antigen.

A single case report described a Thai girl with type I plasminogen deficiency and novel homozygous c.1193G>A (p.Cys398Tyr) (PMID:25281489). The patient presented with ligneous conjunctivitis in infancy, generalized short tooth roots, and mandibular prognathism, implicating plasminogen in normal root dentin formation.

The variant spectrum comprises at least five missense substitutions (e.g., c.1193G>A (p.Cys398Tyr), c.2134G>A (p.Gly712Arg), c.112A>G (p.Lys38Glu), c.1858G>A (p.Ala620Thr)) and splice-site changes, with recurrent alleles in specific populations. No founder variants have been conclusively established, and population carrier frequencies remain low (<0.5%).

Functional studies demonstrate that mutant plasminogen (Ser572Pro) expressed in COS-1 and CHO-K1 cells is retained intracellularly with impaired secretion, explaining plasma deficiency (PMID:8978291). Isoelectric focusing patterns correlate with computer-predicted isoelectric points, confirming that mutant proteins exhibit altered mobility and likely reduced function in vivo (PMID:21537161).

Collectively, biallelic PLG variants validate a loss-of-function mechanism for hypoplasminogenemia. The concordance of genetic and functional data supports a moderate level of clinical validity. Evaluation of plasminogen levels and molecular testing of PLG are essential for diagnosis and genetic counseling. Key take-home: Genetic and functional evidence establish PLG as the causal gene for autosomal recessive hypoplasminogenemia, guiding diagnostic testing and enabling early therapeutic interventions.

References

• Thrombosis and haemostasis • 2004 • Characterization of plasminogen variants in healthy subjects and plasminogen mutants in patients with inherited plasminogen deficiency by isoelectric focusing gel electrophoresis. PMID:15269832
• European Journal of Medical Genetics • 2014 • Root dentin anomaly and a PLG mutation. PMID:25281489
• Blood • 1997 • Molecular pathogenesis of type I congenital plasminogen deficiency: expression of recombinant human mutant plasminogens in mammalian cells. PMID:8978291
• Blood coagulation & fibrinolysis • 2011 • Isoelectric focusing pattern of plasminogen mutants of patients with hypoplasminogenemia: correlation of in-vitro data with computer-predicted isoelectric points (pI). PMID:21537161

Evidence Based Scoring (AI generated)