Compound-Heterozygous Mutations in the Plasminogen Gene Predispose to the Development of Ligneous Conjunctivitis

Abstract

Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 → Glu/Arg513 → His, Lys19 → Glu/Arg216 → His, and Lys19 → Glu/Leu128 → Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (<0.4 mg/dL and <5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity.

Plasminogen deficiency

“…The initial case report linking ligneous conjunctivitis to plasminogen deficiency documented low plasminogen antigen and activity levels [5]. Subsequent reports have consistently documented ligneous lesions in a variety of mucosal areas with hypoplasminogenaemia [1,10,[17][18][19][20][21][22][23].…”

“…Not surprisingly, many of these patients also had ligneous conjunctivitis. Two siblings were reported to develop pseudomembranous plaques in their kidneys [22]. Both patients had numerous other affected areas, including the conjunctiva, gingiva and tracheobronchial tree.…”

Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis

“…Several lines of evidence suggest that fibrin(ogen) itself may be deleterious in many ways. For example, it can mediate and/or enhance inflammation, both acutely and chronically, in arthritis (1–3) and other diseases (19–26).…”

Hypoplasminogenemia With Ligneous Periodontitis: A Failed Local Therapeutic Approach

“…Pseudomembranes also may develop on the mucosa of several organs (mouth, tongue, nasopharynx, pharynx, tracheobronchial tree, and the female genital tract), and in a few cases, congenital obstructive hydrocephalus may occur. [5][6][7][8][9][10][11][12][13][14][15][16] Ligneous conjunctivitis was found to be associated with severe inherited type I plg deficiency for the first time by Mingers et al 1 in 1994. In 1997, Schuster et al 7 demonstrated distinct homozygous and compound-heterozygous mutations in the plg gene and clearly confirmed the autosomal-recessive inheritance of this disorder.…”

“…The theoretically predicted prevalence of homozygotes/compound heterozygotes was estimated to be in the range of 1.6 per 1 million people, at least in Europe. 4,5 Ligneous conjunctivitis is a rare form of chronic conjunctivitis that is characterized by the development of firm, fibrin-rich, woody-like pseudomembranous lesions, mainly on the tarsal conjunctivae. Pseudomembranes also may develop on the mucosa of several organs (mouth, tongue, nasopharynx, pharynx, tracheobronchial tree, and the female genital tract), and in a few cases, congenital obstructive hydrocephalus may occur.…”