Enzyme deficiency from CPN1 gene mutations tied to HAE: Study

Results suggest treatment should be 'adapted' for those with CPN deficiency

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by Andrea Lobo |

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Mutations in the CPN1 gene leading to a deficiency in the activity of the carboxypeptidase N (CPN) enzyme were found in four families with hereditary angioedema (HAE),  according to a new study from Europe.

The team of researchers identified three genetic variants in the CPN1 gene that were associated with family members’ HAE symptoms. CPN1 provides instructions to produce CPN, an enzyme that inactivates bradykinin, the signaling molecule that is thought to drive swelling in HAE.

The results suggest that “CPN deficiency could characterize a group with HAE-CPN, with consequent challenges for patient treatment,” the researchers wrote. Antihistamines did not help ease the  affected patients’ symptoms, “and prophylaxis currently recommended for HAE must therefore be adapted,” the team wrote.

The study, “Hereditary angioedema with normal C1 Inhibitor associated with Carboxypeptidase N deficiency,” was published in the journal JACI Global.

HAE is characterized by recurrent swelling attacks affecting the deeper layers of the skin, mostly in the lips, the skin around the eyes, hands and feet. Swelling episodes also may affect the mucosal linings of the respiratory and digestive tracts.

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Questions about genetics, causes of HAE attacks remain

HAE swelling attacks are thought to be driven by the overproduction of bradykinin, which promotes blood vessel widening and increases their permeability.

The role of genes associated with bradykinin degradation, including CPN1, are not fully understood. And “although the association with genetic variant(s) has been identified for some families, the genetic causes in many patients with HAE-nC1-INH are unknown,” the researchers wrote.

There are several subtypes of HAE, which vary according to mutation. Two major subtypes are HAE with C1 inhibitor deficiency (HAE-C1-INH), which is caused by mutations in the SERPING1 gene, and HAE with normal C1-INH (HAE-nC1-INH), which is caused by mutations in other genes, such as F12.

The team of international researchers described the cases of four families with HAE-nC1-INH and CPN deficiency who had been included in a research program on HAE-nC1-INH. Symptomatic family members mainly had swelling and hives, or urticaria, affecting the face and lips. Some also had abdominal pain.

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Gene mutations, enzyme deficiency tied to HAE symptoms

Antihistamines generally failed to control patients’ symptoms, which tended to ease when they were treated with tranexamic acid and icatibant (sold as Firazyr). Tranexamic acid has been shown to help prevent HAE attacks when used off-label for that purpose, while icatibant is approved to be used as on-demand treatment to manage swelling attacks. Icatibant works by preventing bradykinin from interacting with the receptors to which it normally binds.

“The effectiveness of icatibant on the relief of severe episodes in all four families suggests at least partial involvement of bradykinin in the clinical [characteristics],” the researchers wrote.

C1-INH levels and function were within the normal range in all symptomatic individuals. However, blood CPN activity was 30% to 50% below the median value for healthy individuals.

And CPN1 mutations were associated with the patients’ clinical symptoms and low CPN activity. The researchers were able to identify three CPN1 variants in the region of the gene responsible for encoding a specific subunit of CPN required for the enzyme’s activity: c.533G>A, c.582A>G and c.734C>T.

Our work implicates CPN mutations and enzyme deficiency in contributing to angioedema symptoms in HAE-nC1-INH.

The c.533G>A variant was considered to be a potentially disease-causing mutation when present in both copies of the CPN1 gene, or when combined with either c.582A>G or c.734C>T.

Moreover, CPN1 gene variants combined with variants in other genes previously associated with HAE-nC1-INH, including KLKB1 and F12, that could potentially contribute to chronic HAE symptoms.

“The clinical and genetic records from these four families, in line with the biological findings, are consistent with a hereditary CPN deficiency,” the researchers wrote. “Our work implicates CPN mutations and enzyme deficiency in contributing to angioedema symptoms in HAE-nC1-INH.”