Recently Identified PLG Gene Mutation Found in German Family with HAE, Study Reports

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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KNG1 and XPNPEP1, rare gene variants

A recently described mutation in the plasminogen (PLG) gene has been reported in an additional family in Germany with hereditary angioedema (HAE), highlighting the importance of raising awareness among clinicians for this rare HAE-causing mutation to ensure correct disease diagnosis and treatment, scientists say.

Findings were reported in the study, “Identification of the recently described plasminogen gene mutation p.Lys330Glu in a family from Northern Germany with hereditary angioedema,” which was published in Clinical and Translational Allergy.

Hereditary angioedema is a rare, genetic disorder characterized by sudden and recurrent episodes of swelling in the face, tongue, hands, feet, gastrointestinal (GI) tract, genitalia, and upper airways.

“Anti-allergic drugs, i.e. antihistamines, corticosteroids and epinephrine, which are administered in histamine-mediated angioedema, are not effective in the treatment of HAE. Therefore, a correct and early diagnosis is of utmost importance for affected individuals in order to transfer them to specialized medical centers and to provide effective emergency medications,” the investigators wrote.

HAE types 1 and 2 are caused by genetic mutations in the SERPING1 gene, leading to lower levels of C1 inhibitor (C1-INH) protein, in the case of type 1, or to a dysfunctional C1-INH protein, in the case of type 2. Conversely, HAE type 3 is normally associated with mutations in the coagulation factor XII (F12) gene, and the levels of C1-INH protein remain normal.

In this study, a group of scientists from the University of Lübeck in Germany described the case of a German family with six individuals who experienced recurrent episodes of swelling suggestive of HAE.

Lab tests and genetic screenings failed to identify genetic mutations in both SERPING1 and F12. However, in three members of the family experiencing recurrent swelling episodes, and in another without symptoms, investigators identified a mutation, known as c.988A > G, in the PLG gene, which provides instructions to make the liver protein plasminogen.

The c.988A > G mutation, also known as c.1100A > G, is a missense (a single nucleotide mutation that alters protein composition) mutation that had been recently described in several families with HAE. But investigators report that no direct relationship existed between the cases previously described in the literature and the family from northern Germany analyzed in this study.

In all family members carrying the mutation, symptoms only started in adulthood, and included swelling of the face, tongue, and larynx (vocal cords). The frequency of the swelling episodes was extremely variable, ranging from once per year to once per month. In one member of the family, the researchers also found abnormally low levels of plasminogen and F12 in the serum.

“Comparing our family with the recently published patients with HAE associated with a PLG gene mutation (HAE-PLG), the age of onset, clinical presentation and frequency of angioedema of all affected members of our family are in line with these previous reports.  With our family, there are now 24 unrelated families from different countries with HAE-PLG with 105 affected individuals,” the researchers wrote.

As previously reported in other patients with mutations in the PLG gene, all family members responded well to treatment with Firazyr (icatibant) during acute attacks, suggesting that bradykinin — a protein that causes blood vessels’ dilation and tissue swelling  — may be involved in HAE-PLG.

“HAE-nC1-INH [HAE with normal C1-INH levels or function] is a life-threatening disease that is lacking appropriate biomarkers [and is still] difficult to diagnose. Therefore, it is of importance to sensitize physicians for this rare and severe, but treatable disease,” which can be easily mistaken for an acquired angioedema or angioedema caused by blood pressure medications, the researchers said.

They added that clinical trials are now needed to investigate if treatments available for HAE with deficient C1-INH — such as BCX7353, avoralstat, Kalbitor (ecallantide), Ruconest (conestat alfa), the purified C1-INH products Haegarda, Cinryze, and Berinert, and the antibody inhibiting kallikrein Takhzyro (lanadelumab) — are also effective for these patients.