Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


HAE types I, II and III (hereditary angioneurotic edema; C1 inhibitor deficiency) Hereditary Angioedema types I, II, and III (Hereditary angioneurotic edema; C1 Inhibitor Deficiency) - Genes SERPING1 and F2.

Angioedema or hereditary angioneurotic edema (HANE: Hereditary angioneurotic edema), is a disease characterized by episodic swelling of the lips, face, intestinal tract or airways. Intestinal involvement manifests with abdominal swelling, nausea and vomiting. The airway edema may affect breathing, causing obstruction of the airways. Approximately 30% of patients may have a non - pruritic rash called "Erythema marginatum". These episodes may be triggered by minor trauma, but sometimes the triggering cause is not known. Have identified three types of angioedema, type I, II and III as the underlying genetic causes and blood concentration of C1 inhibitor protein (C1INH). Type I is the most common (85% of cases), followed by type II (15%) and type III (rare).

The angioedemas types I and II, are due to mutations in the gene SERPING1 (Serpin peptidase Inhibitor clade G -C1 inhibitor-, member 1; before Serin proteinase inhibitor clade -OR cystein- -C1 inhibitor- G, member 1), located in long arm of chromosome 11 (11q12.1). This gene encodes the protein C1 inhibitor (C1INH), which controls inflammation by blocking the activity of proteins that promote it .

There are more than 250 mutations in the gene SERPING1. Mutations causing the type I cause a reduction in blood concentration of C1INH, while mutations that give rise to type II are generally produced in exon 8 of the gene SERPING1 and result encoding a protein C1INH altered, that It does not operate normally. No concentrations, or proper function of C1INH, excessive amounts of vasoactive peptide bradykinin called are generated. Furthermore, no action of C1s fraction of the complement system is inhibited, the main function of C1INH. The C1s fraction is generated from the component C1 of the complement system, when the classical pathway is activated upon interaction of antibodies with their corresponding antigens. As a result, excessive amounts of C3a and C5a have vasoactive effect fractions are generated. The C1INH protein also blocks plasma kallikrein and activated factor XII (XIIa). Both kallikrein and factor XIIa, participate in the formation of bradykinin, the protein that promotes increased vascular permeability existing in inflammatory phenomena, due to increased fluid output to extravascular space through the walls of blood vessels. When there is not enough C1INH synthesis, or their function is impaired, plasma kallikrein is not inhibited, nor the XIIa factor crashes. The extravascular fluid accumulation, by any of the foregoing, causes episodes of swelling (edema).

The (rare) type III angioedema, is due to mutations in the F2 gene, located on the long arm of chromosome 5 (5q35.3). This gene encodes the protein synthesis coagulation factor XII. The coagulation factor XII, when (factor XIIa) is activated, in addition to participating in blood coagulation, is a stimulator of inflammation involved in the generation of bradykinin. For this purpose, factor XIIa acts upon prekallikrein plasma protein, transforming it into kallikrein, and it generates the production of bradykinin. They have identified at least two mutations in the F2 gene in people with type III angioedema. These mutations change the amino acids XII factor, which increases the activity of the protein. As a result, as many bradykinin, which in turn is causing inflammation by increasing vascular permeability is generated.

These processes have an autosomal dominant, which means that an altered copy of the gene in each cell is sufficient to cause the alteration. In some affected inherit the mutation from one parent, but others are due to new mutations that occur in individuals with no family history of genetic disease.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with angioedema, by complete PCR amplification of the exons of SERPING1 (angioedemas types I and II) and F2 (type III angioedema) genes, respectively, and subsequent sequencing .

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).