Mutation Found in PLG Gene May Represent New Type of HAE, Study Suggests

A newly identified mutation in the plasminogen (PLG) gene is associated with a characteristic hereditary angioedema (HAE) phenotype and may represent a new HAE subtype, a German study reports.

The research, “A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor,” appeared in the journal Biochemical and Biophysical Research Communications.

The complement system is a part of the immune system that plays a key role in inflammation and in defending against some bacterial infections.

Classical types of HAE — types I and II — are caused by mutations in the complement C1 inhibitor gene, which result in a deficient or altered C1 inhibitor (C1-INH). This protein prevents the activity of complement component C1 and other enzymes involved in clotting.

But HAE can also be found in patients with normal C1-INH levels and activity; these people have the so-called HAE type III. Although the molecular basis of type III HAE remains largely unknown, research has shown that a subset of patients have mutations in the coagulation factor XII (F12) gene.

To better understand what causes HAE in people with normal C1-INH, Georg Dewald, a scientist at the Institute for Molecular and Preventive Medicine in Germany, screened eight unrelated patients without F12 mutations, corresponding to eight large families, to focus specifically on the PLG gene. The PLG protein is produced in the liver and released to the blood, where it plays a crucial role in breaking down clots.

Results revealed a rare missense mutation in the PLG gene in three patients, but not in any of 139 people serving as controls. Missense mutations are single changes in nucleotides — the building blocks of DNA or RNA — that result in a different amino acid in the final protein.

Specifically, the PLG mutation found in the three predicts a substitution of lysine by glutamic acid, both amino acids. Dewald then observed that this mutation was linked the presence of a plasminogen protein with an abnormal structure and function. He suggested the mutation could alter the affinity of plasminogen to its binding partners, and possibly lead to novel interactions.

These three families had 18 members — 13 women and five men — with HAE with normal C1-INH. Angioedema attacks of the tongue were observed in 89% of them. These attacks differ from other HAE types, where tongue swellings are either rare or seen in less than half of the patients, Dewald wrote.

Collectively, the mutation’s impact on the protein, its absence in the control group, and the link to disease phenotype all support that this mutation defines a new type of HAE, the researcher said. “One may use the term ‘HAE type C’ for the HAE subentity described here, for a hereditary angioedema caused by a mutation of the plasminogen gene,” Dewald wrote.

“In conclusion, the present findings are expected to have immediate impact on the management of patients with recurrent angioedema and normal C1 inhibitor, not only with respect to their diagnostic evaluation, but also with respect to more specific considerations about the use of eventually available therapeutic options,” his study concluded.