New Gene Mutation Linked to HAE Type 1 Identified in Spanish Family
A new mutation in the SERPING1 gene linked to hereditary angioedema (HAE) type 1 was identified in three of five members of a Spanish family.
Results were published in a letter to the editor of the journal Pediatric Allergy and Immunology titled “Hereditary angioedema caused by a novel intronic variant of SERPING1.”
HAE is a form of angioedema caused by genetic mutations. The most common form of HAE, HAE type 1, is caused by mutations in the SERPING1 gene, which provides instructions for making a protein called C1 inhibitor, or C1-INH.
This protein prevents the spontaneous activation of the complement system — a signaling cascade involved in the body’s inflammatory response — and regulates other signaling pathways that control blood clotting and inflammation.
HAE type 1 also is characterized by low levels of C4, a component of the complement cascade, but normal levels of C3.
HAE diagnosis is hampered by the fact that 25% of the cases are caused by the so-called de novo mutations, which are those that are not inherited. Moreover, in up to 10% of the cases, disease-causing mutations remain unknown.
In this letter to the editor, a group of researchers at the Hospital Universitario Central de Asturias, in Oviedo, Spain, described a family with HAE type 1 caused by a mutation that had never been described.
The family was composed by five members, a grandmother, mother, father, and two children — an 11-month-old girl and a 3-year-old boy. Both grandmother and mother were previously diagnosed with HAE type 1 based on clinical symptoms and lab tests.
Symptoms included recurrent swelling episodes and low C1-INH levels in the bloodstream. The girl presented swelling of the eyelid during an infection, while the boy had no symptoms.
The researchers measured the levels and activity of C1-INH, as well as the levels of C3, C4, and C1q in the mother and both children.
C3 and C1q levels were normal, while C4 and C1-INH levels were low. C1-INH activity also was reduced.
A genetic analysis revealed the girl carried a new mutation located in an intron of the SERPING1 gene. Introns are portions of genes that do not contain information to make proteins and are normally removed during protein production.
Researchers then looked for the new mutation in the other family members and found that it was present in one of the two copies of the SERPING1 gene in the mother and the brother.
The mutation, the researchers believe, led to the formation of a shorter, nonfunctional version of the C1-INH protein, which “probably causes a decrease in the expression [production] of the full-length protein, thus reducing the normal C1 INH activity.”