An update on the genetics and pathogenesis of hereditary angioedema

Abstract

Hereditary angioedema (HAE) is an uncommon genetic disorder characterized by recurrent episodes of edema involving subcutaneous tissue and submucosa. The pathogenesis of HAE reflects an intricate coordinated regulation of components of complement, kinin and hemostatic pathway. Till date, mutations in 4 different genes have been identified to cause HAE which includes serine protease inhibitor G1 (SERPING1), factor XII (F12), plasminogen (PLG) and angiopoietin 1 (ANGPT 1). These mutations lead to increased bradykinin 2 receptor mediated signalling via increased production of bradykinin except mutations in ANGPT1 gene that disturbs the cytoskeletal assembly of vascular endothelial cells. In this review we aim to summarize the recent advances in the pathogenesis and genetics of HAE. We also provide an overview of possible future prospects in the identification of new genetic defects in HAE.

Keywords: Angiopoietin 1; C1 inhibitor; Factor XII; Genetics; Hereditary angioedema; Plasminogen.

Figure 1

A simplified summary of the kinin metabolism and the mutual interactions between the kinin, complement, hemostatic and fibrinolytic pathways. (The blue arrows represent the augmentation of the enzymatic reactions shown in brown arrows). The sites of action of C1 esterase inhibitor (C1-INH) are represented in green chevron shapes). Abbreviations: FXII – Factor XII, a as a suffix indicates the active form; pK – prekallikrien; K (in bold) – kallikrien; HMWK – high molecular weight kininogen; LMWK – low molecular weight kininogen; BK – bradykinin; KD – kallidin (lysine-bradykinin: K-BK), BK_2-9 – bradykinin with its first amino acid cleaved off; BK_1-7 – bradykinin with its last two amino acids cleaved off; Des-R BK – bradykinin with its ninth arginine residue cleaved off; meaning of subscripts in case of kallidin (K-BK) is the same as that for bradykinin derivatives; ACE (also called kininase II) – angiotensinogen converting enzyme, AP – aminopeptidase, K I – kininase I.

Figure 2

Summary of the genetic defects leading to the phenotype of hereditary angioedema. HAE-1 (Type 1) is due to mutations leading to a quantitative defect of C1 esterase, whereas HAE-2 (Type 2) represents qualitative defects of C1-INH function. HAE-FXII and HAE-PLG pertains to defects in factor XII and plasminogen respectively. HAE-ANGPT1 corresponds to the recently described defects in the angiopoietin-1 gene leading to a hereditary angioedema like phenotype, whereas HAE-UI represents still unidentified mutations.

Figure 3

Various mutations reported in SERPING1 gene.

Figure 4

Counteracting influences of angiopoietin 1 and bradykinin on vascular endothelial cells. Angiopoietin 1 acting via TIE 2 receptor reinforces the cell cytoskeletal arrangements and decreases the vascular permeability. While, bradykinin disrupts this orderly arrangement leading to increased vascular permeability.

Figure 5

Proposed diagnostic algorithm for evaluation of a suspected case of hereditary angioedema (HAE with normal C1 inhibitor function requires genetic analysis for diagnosis).

Figure 6

Therapeutic modalities employed in the management of hereditary angioedema. (The blue arrows represent the augmentation of the enzymatic reactions shown in brown arrows; the green arrows with a plus sign indicate therapies for replacement or augmentation of the target product, while the red arrows with a minus sign indicate inhibitions. The sites of action of C1 esterase inhibitor (C1-INH) are represented in green chevron shapes). Abbreviations: FXII – Factor XII, a as a suffix indicates the active form; pK – prekallikrien; K (in bold) – kallikrien; HMWK – high molecular weight kininogen; LMWK – low molecular weight kininogen; BK – bradykinin; KD – kallidin (lysine-bradykinin: K-BK), BK_2-9 – bradykinin with its first amino acid cleaved off; BK_1-7 – bradykinin with its last two amino acids cleaved off; ACE (also called kininase II) – angiotensinogen converting enzyme, AP – aminopeptidase, K I – kininase I, TA – tranexamic acid, EACA – epsilon amino caproic acid.