PLG – Hereditary Angioedema

Hereditary angioedema (HAE) is a potentially life-threatening bradykinin-mediated disorder characterized by recurrent episodes of subcutaneous and mucosal swellings, including facial, tongue, and laryngeal edema, as well as abdominal cramping. While most HAE cases involve C1-INH deficiency, non-C1-INH forms have been linked to mutations in genes such as F12 and PLG. The discovery of a heterozygous PLG c.988A>G (p.Lys330Glu) variant has established a distinct autosomal dominant subtype, HAE-PLG, underscoring the need for genetic testing in patients with normal C1-INH levels and unexplained angioedema.

Genetic evidence for PLG involvement in HAE includes at least 11 probands across 5 unrelated families, with the c.988A>G (p.Lys330Glu) variant identified in heterozygous form in all affected individuals and absent in unaffected relatives (PMID:30809376; PMID:29548426; PMID:36418094). In a Northern German pedigree, three affected and no unaffected relatives harbored the variant, demonstrating segregation with disease (PMID:30809376). Additional co-segregation was observed in three large families of European and Asian descent (PMID:29548426; PMID:36418094).

The variant spectrum in HAE-PLG is dominated by the recurrent missense change c.988A>G (p.Lys330Glu), which localizes to the kringle 3 domain of plasminogen and has been found in 5 independent cohorts. To date, no loss-of-function or structural variants in PLG have been associated with HAE, and no founder haplotypes have been reported, indicating a mutational hotspot rather than population-specific alleles.

Functional studies support a gain-of-function mechanism. Structural modeling and in vitro assays with purified proteins confirm that p.Lys330Glu enhances direct cleavage of high-molecular-weight kininogen to release bradykinin, bypassing the classical FXII/kallikrein pathway (PMID:36685169). Clinically, acute attacks in HAE-PLG patients respond robustly to the bradykinin B2 receptor antagonist icatibant, further implicating bradykinin overproduction in pathogenesis (PMID:30809376).

No studies to date have refuted the association between PLG p.Lys330Glu and HAE or demonstrated significant phenotypic variability inconsistent with this mechanism. The consistent clinical phenotype across multiple families and concordant functional data yield no conflicting evidence.

Collectively, autosomal dominant inheritance of a recurrent PLG missense variant, segregation in multiple families, and mechanistic gain-of-function data establish a Strong gene–disease relationship for PLG and Hereditary Angioedema. Key Take-home: Testing for PLG c.988A>G should be incorporated into diagnostic workflows for patients with unexplained HAE and normal C1-INH levels to guide appropriate bradykinin-targeted therapies.

References

• Clinical and Translational Allergy • 2019 • Identification of the recently described plasminogen gene mutation p.Lys330Glu in a family from Northern Germany with hereditary angioedema. PMID:30809376
• Biochemical and Biophysical Research Communications • 2018 • A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor. PMID:29548426
• Internal Medicine (Tokyo, Japan) • 2023 • A Missense Mutation of the Plasminogen Gene in a Japanese Family with Hereditary Angioedema with Normal C1 Inhibitor: Third Family Survey in Asia. PMID:36418094
• Frontiers in Physiology • 2022 • Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin. PMID:36685169

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