Japanese Researchers Identify New Gene Mutation Linked to HAE

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Japanese researchers have identified a new mutation in the SERPING1 gene linked to hereditary angioedema (HAE) in a 27-year-old woman with a history of recurrent swelling attacks.

Her case was described in a report, “Hereditary angioedema with a novel mutation, c.1481G>C, in the SERPING1 gene,” published in the Journal of Cutaneous Immunology and Allergy.

HAE types 1 and 2 are caused by the lack of functional C1 inhibitor (C1-INH) protein, as a result of mutations in the SERPING1 gene. This protein normally blocks the activity of other proteins involved in blood clotting and inflammation, including plasma kallikrein. In the absence of functional C1-INH, plasma kallikrein continually produces bradykinin, an inflammatory molecule that promotes blood vessel dilation and fluid leakage, resulting in swelling.

The disease is characterized by sudden and recurrent episodes of swelling, which can affect the face, tongue, hands, feet, gastrointestinal tract, genitalia, and upper airways.

To date, more than 450 HAE-causing mutations in the SERPING1 gene have been identified. Yet, the specific disease manifestations associated with each mutation are not known.

In the report, researchers in Japan described the case of a 27-year-old woman with a long history of recurrent swelling episodes in her extremities, who was later found to have HAE and carry a new mutation in the SERPING1 gene.

Her first swelling episode, which occurred in one of her thighs, happened during childhood. Later, in her early 20s, she experienced swelling on her hands and feet once every few months, which resolved within a few days. Fatigue, cold, or carrying heavy loads were deemed potential triggers for these attacks.

She also complained of abdominal pain after exercise, but never experienced swelling on her face or throat.

Her mother and her mother’s father experienced similar symptoms, but they had not been diagnosed or treated.

When the woman started experiencing these attacks more often — over three times a month — she decided to visit the hospital.

Blood tests showed the activity of the C1-INH protein — the gold-standard diagnostic test for HAE — was notably reduced, at 16% (normal range: 70%–130%). Also, the levels of the complement C4 protein were 3.1 milligrams per deciliter (mg/dL), which were below the normal range of 10.6–33.0 mg/dL.

Genetic testing revealed the patient carried a new mutation, called c.1481G>C, in the SERPING1 gene, which was located in the gene’s exon eight. Exons are regions within a gene that contain instructions to make a protein.

This mutation was also found to cause an amino acid — the building blocks of proteins — to be replaced by another in the C1-INH protein sequence. More specifically, an arginine to be replaced by proline on position 494 of the protein sequence (p.Arg494Pro).

Despite being a heterozygous mutation, meaning that it was present in only one of the two copies of the SERPING1 gene, it significantly reduced the activity of the C1-INH protein.

At this point, the patient was diagnosed with HAE and prescribed icatibant (sold as Firazyr). Because the patient did not develop serious attacks, self-administration of icatibant was not required.

“As HAE is rare but potentially fatal, early diagnosis and appropriate treatment are essential,” the researchers wrote. “We believe that accumulation of gene mutations and clinical reports will facilitate further elucidation of disease pathogenesis [development] and the development of more effective care for HAE.”