Kininogen-1 (KNG1) (KNG1)

Kininogen-1 (KNG1) is a multi-functional plasma protein that serves as a critical precursor in the kallikrein-kinin system [1, 2]. Through alternative splicing, the KNG1 gene produces two primary isoforms: high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK) [1]. LMWK is primarily cleaved by tissue kallikreins to release kallidin (lysyl-bradykinin), a potent vasodilator that modulates local blood pressure and inflammatory responses [4, 5]. Beyond its role as a kinin source, LMWK functions as a potent inhibitor of cysteine proteases, such as cathepsins, helping to regulate proteolytic activity in various tissues [1]. In clinical medicine, KNG1 is a significant therapeutic target for hereditary angioedema (HAE), a condition characterized by excessive bradykinin production leading to severe swelling [3]. Modern therapeutic approaches, such as the antisense oligonucleotide donidalorsen, target KNG1 mRNA to reduce the overall production of kininogens, thereby limiting the substrate available for kinin generation and preventing angioedema attacks [3]. References: [1] UniProt (P01042); [2] NCBI Gene (3827); [3] Riedl et al. (2024) NEJM; [4] StatPearls, Kallikrein-Kinin System; [5] Schmaier (2016) JTH.

Other names

Low molecular weight kininogenLMWKHigh molecular weight kininogenHMWKAlpha-2-thiol proteinase inhibitorFitzgerald factorWilliams-Fitzgerald-Flaujeac factor

Antisense oligonucleotide-mediated reduction of KNG1 mRNA levels to decrease the production of kininogen proteins and their downstream inflammatory kinin products [3].