KNG1 Gene

The KNG1 gene (KNG1 stands for kininogen 1) is a protein-coding gene located on chromosome 3q27.3. Three transcript variants encoding different isoforms have been found for this gene. The KNG1 gene produces by alternative splicing two different proteins

• high molecular weight kininogen (HMWK)

and

• low molecular weight kininogen (LMWK).

HMWK is important for blood clotting and the assembly of the kallikrein-kinin system. In addition, HMWK releases bradykinin, a peptide with numerous physiological effects. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal effects. Unlike HMWK, LMWK is not involved in blood clotting.

Kininogens are inhibitors of thiol proteases. HMW kininogen plays an important role in blood coagulation by helping to optimally position prekallikrein and factor XI next to factor XII. HMW-kininogen inhibits thrombin- and plasmin-induced aggregation of platelets. The active peptide bradykinin released from HMW kininogen exhibits a variety of physiological effects: such as a cardioprotective effect (directly via the action of bradykinin, indirectly via the action of endothelium-derived relaxing factor; LMW kininogen inhibits platelet aggregation). LMW kininogen, unlike HMW kininogen, is not involved in blood clotting.

Diseases associated with KNG1 include:

• Hereditary angioedema type 6 (hereditary angioedema mutation in KGN1)

and

• High-molecular-weight (HMW) kininogen deficiency.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection reduces or depletes angiotensin-converting enzyme 2 (ACE2), leading to an increase in des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin associated with lung injury and inflammation.

1. Bork K et al. (2019) Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. (Letter) Allergy 74: 2479-2544.
2. Hayashi H et al. (1990) Molecular genetic survey of five Japanese families with high molecular weight kininogen deficiency. Blood 75: 1296-1304.
3. Krijanovski Y et al. (2003) Characterization of molecular defects of Fitzgerald trait and another novel high-molecular-weight kininogen-deficient patient: insights into structural requirements for kininogen expression. Blood 101: 4430-4436.
4. Lefrere JJ et al (1986) A new case of high molecular weight kininogen inherited deficiency. Am J Hemat 22: 415-419.
5. Loules G et al (2020) Deciphering the genetics of primary angioedema with normal levels of C1 inhibitor. J Clin Med 9: 3402.