rs73015965 — PLG Lys38Glu (K38E)

PLG Lys38Glu — When Fibrin Clogs the Ear Canal

Plasminogen is the body's master clot-dissolving precursor. Secreted by the liver and distributed throughout the bloodstream and mucosal tissues, it is activated to plasmin¹¹ plasmin
the active serine protease that cleaves fibrin, dissolves clots, and clears debris from injured mucosal surfaces wherever the body needs to remodel or repair tissue. In the middle ear, this fibrinolytic activity is essential — infections naturally produce fibrin as part of the inflammatory response, and plasmin dissolves it before it accumulates into permanent, obstructive deposits.

The Lys38Glu variant (c.112A>G, historically called K19E before signal peptide corrections standardized numbering) swaps a positively charged lysine for a negatively charged glutamic acid at position 38 of the mature protein, located in the PAN/Apple domain. This is the most common disease-causing mutation in the PLG gene worldwide, found in 34% of alleles among documented plasminogen deficiency patients. The variant impairs the protein's secretion from liver cells — mutant plasminogen is retained and degraded rather than efficiently released into circulation — leaving mucosal surfaces chronically short of the fibrinolytic activity they need.

The Mechanism

When plasminogen levels fall sufficiently, fibrin cannot be cleared from inflamed mucosal surfaces at the rate it is deposited. The result is the accumulation of ligneous (woody) pseudomembranes²² ligneous (woody) pseudomembranes
thick, fibrin-rich masses that replace normal mucosal tissue with a wood-like material; "ligneous" derives from the Latin for wood, describing their texture. In the middle ear, uncleaned fibrin creates an ideal matrix for bacterial colonization and chronic infection. In mouse models, complete plasminogen deficiency causes 100% of animals to develop chronic otitis media³³ complete plasminogen deficiency causes 100% of animals to develop chronic otitis media
with bacterial colonization by five different species, extensive fibrin deposition, and neutrophil/macrophage infiltration — all within 18 weeks.

The Lys38Glu variant in humans is not a null allele — heterozygous carriers have residual plasminogen activity and mostly do not develop overt ligneous disease. The clinical spectrum runs from asymptomatic carriers (one functional copy is usually enough for adequate fibrinolysis) through increased susceptibility to recurrent otitis media, to severe ligneous conjunctivitis and other mucosal pseudomembranes in compound heterozygotes or homozygotes who carry two loss-of-function alleles.

The Evidence

The landmark clinical series by Tefs et al. in Blood (2006), covering 50 patients with confirmed type I plasminogen deficiency⁴⁴ Tefs et al. in Blood (2006), covering 50 patients with confirmed type I plasminogen deficiency
largest cohort study to date, across multiple countries, established Lys38Glu as the most prevalent disease allele worldwide (34% of pathogenic PLG alleles in the cohort). Otitis media was a documented manifestation in 14% of these patients — the fourth most common mucosal site after eyes (80%), gums (34%), and respiratory tract (16%).

At the population level, the 23andMe GWAS of over 200,000 Europeans identified the PLG locus as genome-wide significantly associated with childhood ear infection susceptibility⁵⁵ identified the PLG locus as genome-wide significantly associated with childhood ear infection susceptibility
OR=1.43, p<5×10⁻⁸, from the landmark 2017 Nature Communications GWAS of 23 common infections. An OR of 1.43 is unusually high for a common infection GWAS — most GWAS hits for infectious disease susceptibility show ORs in the 1.1–1.2 range — reflecting the direct mechanistic link between PLG function and middle ear fibrin clearance.

A targeted multi-omic study of 718 otitis-prone families identified the Lys38Glu variant in four multi-ethnic families showing an autosomal dominant pattern with reduced penetrance⁶⁶ identified the Lys38Glu variant in four multi-ethnic families showing an autosomal dominant pattern with reduced penetrance
Bootpetch et al., Scientific Reports 2020, reinforcing the biological plausibility even though the smaller family-based TDT did not reach statistical significance.

In the clinical setting, type I plasminogen deficiency is diagnosed in approximately 1.6 per million individuals⁷⁷ type I plasminogen deficiency is diagnosed in approximately 1.6 per million individuals
Shapiro & Nakar, Blood 2025, with the diagnosis frequently delayed because early presentations mimic common conditions — clinicians often attribute repeated ear infections to Eustachian tube dysfunction, adenoid hypertrophy, or daycare exposure before the underlying fibrinolytic defect is recognized.

Practical Implications

For carriers of a single Lys38Glu allele (AG genotype), the risk is a modest elevation in recurrent ear infection susceptibility, not overt plasminogen deficiency. One functional PLG copy is generally sufficient to maintain near-normal fibrinolysis; the association observed in the GWAS likely reflects heterozygous dosage effects on mucosal fibrin clearance during infections.

For those with two risk alleles (GG) or those who are compound heterozygotes (one Lys38Glu allele plus a different loss-of-function PLG allele not captured by this SNP), the clinical picture shifts significantly: plasminogen levels can fall to 5–17% of normal, and ligneous pseudomembranes can form across multiple mucosal surfaces simultaneously. The FDA approved an intravenous human plasma-derived plasminogen concentrate (Ryplazim) in 2021 — the first specific treatment for this condition.

Recurrent otitis media in a child with an ear infection history that seems disproportionate to typical risk factors — particularly if there are also eye, gum, or respiratory membrane abnormalities — warrants plasminogen level testing.

Interactions

The pathogenicity of Lys38Glu depends strongly on the status of the second PLG allele. Compound heterozygosity — carrying Lys38Glu on one chromosome and a different pathogenic PLG mutation (stop, frameshift, splice site, or other missense) on the other — produces much lower residual plasminogen activity than heterozygosity for Lys38Glu alone. Individuals in families with known plasminogen deficiency should consider comprehensive PLG sequencing rather than relying on this single rsid to characterize their risk.

No gene-gene interaction compound actions are proposed at this time, as the primary clinical modifier is the second PLG allele (not captured in a single-variant GWAS entry).