Homozygous Mutations in the Plasminogen Gene of Two Unrelated Girls With Ligneous Conjunctivitis

Abstract

Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis that usually starts in early infancy. The disease may be associated with pseudomembranous lesions of other mucous membranes in the mouth, nasopharynx, trachea, and female genital tract. We examined two unrelated Turkish girls both suffering from ligneous conjunctivitis and occlusive hydrocephalus. Both children exhibited a severe plasminogen deficiency. Genomic DNA from both patients as well as from clinically healthy family members were screened for mutations in the plasminogen gene by polymerase chain reaction, single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. In the first girl with ligneous conjunctivitis a homozygous G → A point mutation was identified in plasminogen exon 7 at position 780 leading to an amino acid exchange (Arg216 → His). Her healthy sister and her healthy parents were heterozygous for this mutation. The second patient revealed a homozygous G → A point mutation in plasminogen exon 15 at position 1924 which leads to a stopcodon (Trp597 → Stop). The healthy parents were shown to be heterozygous for this mutation. In addition, the father's second allele revealed another mutation in the same codon (Trp597 → Cys) (compound heterozygosity). In conclusion, certain homozygous mutations in the plasminogen gene may cause ligneous conjunctivitis.

Ligneous conjunctivitis in a plasminogen‐deficient dog: clinical management and 2‐year follow‐up

“…To our knowledge, this is the first case report of a dog with PLG deficiency and LC with a long survival period and 2‐year follow‐up. Future studies will be needed to focus on the inheritability of the disease and mutations in the PLG gene; in human medicine an autosomal recessive inheritance is suspected, associated with a mutation in the long arm of chromosome 6 or 2 9,23,32,39 . In canine patients due to the low number of cases reported, no inheritability has as yet been proven, so further familial investigation of affected dogs is needed.…”

“…It usually begins after local injury and is caused by a systemic plasminogen disorder 8 . Although the disease may appear at any gender and at any age, a clear sexual predisposition in young females has been described 1,3,4,9–20 . Usually the disease starts in early infancy, with conjunctival redness that progress to pseudomembranes formation on the palpebral conjunctival surface.…”

Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice

“…The demonstration of a third Plg activator, which at least partially accounts for the difference in wound healing time between uPA;tPA ‐deficient and Plg ‐deficient mice, has important implications for the understanding of Plg activation during normal and pathological tissue remodelling. It is well established that Plg deficiency results in serious physiological consequences in both humans and mice although with different degrees of penetrance (Bugge et al , 1995; Schuster et al , 1997; Drew et al , 1998). In several fundamental physiological processes involving normal as well as pathological tissue remodelling, Plg activation has been shown to play a pivotal role, and it will be interesting to define the individual and combined significance of uPA, tPA and pKal.…”

Functional overlap between two classes of matrix-degrading proteases in wound healing

“…Recently, the rare, but long known and well described, inherited disease ligneous conjunctivitis was linked to Plg deficiency (Mingers et al ., 1997; Schuster et al ., 1997, 1999; Schott et al ., 1998). This disease is characterized by pseudomembranous ‘wood‐like’ lesions of the conjunctiva and other mucous membranes (Bouisson et al ., 1847; Bateman et al ., 1986; Hydayat et al ., 1987; Schuster et al ., 1997), and there are many similarities with the phenotype observed in the Plg‐deficient mice (Bugge et al ., 1995a; Ploplis et al ., 1995; Rømer et al ., 1996; Drew et al ., 1998), including the impaired wound healing which was recently described in two patients with inherited Plg deficiency (Mingers et al ., 1997; Schott et al ., 1998). Ligneous conjunctivitis patients often display serious symptoms, such as hydrocephalus and blindness, indicating that long‐term use of effective plasmin inhibitors for therapeutic purposes, including the treatment of cancer patients, may not be feasible due to severe side effects.…”