Screening for Plasminogen Mutations in Hereditary Angioedema Patients

Abstract

Hereditary angioedema (HAE) is a rare disease belonging to the group of bradykinin-mediated angioedemas, characterized by recurring edematous episodes involving the subcutaneous and/or submucosal tissues. Most cases of HAE are caused by mutations in the SERPING1 gene encoding C1-inhibitor (C1-INH-HAE); however, mutation analysis identified seven further types of HAE: HAE with Factor XII mutation (FXII-HAE), with plasminogen gene mutation (PLG-HAE), with angiopoietin-1 gene mutation (ANGPT1-HAE), with kininogen-1 gene mutation (KNG1-HAE), with a myoferlin gene mutation (MYOF-HAE), with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation, and hereditary angioedema of unknown origin (U-HAE). We sequenced DNA samples stored from 124 U-HAE patients in the biorepository for exon 9 of the PLG gene. One of the 124 subjects carried the mutation causing a lysine to glutamic acid amino acid exchange at position 330 (K330E). Later, the same PLG mutation was identified in the patient’s son. The introduction of new techniques into genetic testing has increased the number of genes identified. As shown by this study, a biorepository creates the means for the ex-post analysis of recently identified genes in stored DNA samples of the patients. This makes the diagnosis more accurate with the possibility of subsequent family screening and the introduction of appropriate therapy.

The Missing Link: A Case of Severe Adverse Reaction to Histamine in Food and Beverages

“…HAE can be divided into subgroups depending on the levels of C1 inhibitor (C1-INH): HAE with normal levels of C1-INH and HAE with C1-INH deficiency (type 1 and 2). The latter (C1-INH-HAE) is caused by the autosomal dominant mutation of the SERPING1 gene encoding C1-inhibitor [ 20 ]. Patients with HAE may show abnormal complement system laboratory findings [ 21 ], but routine laboratory tests show no abnormalities.…”

A novel plasminogen mutation in a child with hereditary periodic syndrome: A case report

“…For hereditary angioedema, there is evidence of incomplete penetrance in the literature, as highlighted by two recent reports in which heterozygous mutations were uncovered in a symptomatic parent as well as their asymptomatic son or daughter. 18,19 Similarly, for PLG deficiency, there are reports of patients with homozygous or compound heterozygous PLG mutations, along with severely depressed PLG activity levels (<10%) who were clinically healthy. 20,21 A recent report described a patient with ligneous conjunctivitis and reduced PLG levels.…”

Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology

“…Elevated estrogen levels correspond with increased factor XIIa levels which, using the previously mentioned positive feedback loop, increase bradykinin levels [36]. Current guidelines now recommend subdividing Hereditary Angioedema with Normal C1 esterase inhibitor gene (HAE-nl-C1-INH formerly known as HAE type III) based on underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene mutation (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), a mutation in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1) [16][17][18].…”

“…Type III HAE, resulting from a normal C1-INH function, is not fully understood. Type III HAE has been shown to result in elevated estrogen levels, which also increases levels of activated factor XII, and has a variety of other mutations that can be seen in this subtype [ 13 , 15 , 16 ]. More recent guidelines suggest classifying all HAE-nl-C1-INH based on specific mutations [ 17 ].…”