KLKB1 (Plasma Prekallikrein / Bradykinin Contact System Gene)
KLKB1 (kallikrein B1; HGNC:6371, NCBI Gene ID 3818) is a human locus mapped to chromosome band 4q35.2 that encodes plasma prekallikrein zymogen (619 mature aa) cleaved by Factor XIIa into active Plasma Kallikrein (EC 3.4.21.34). KLKB1 acts in contact activation system & high-molecular-weight kininogen cleavage to bradykinin, together with CRISPR-Cas9 Genome Editing, Guide RNA (gRNA / sgRNA), and Antisense Oligonucleotides (ASOs). Encodes hepatic plasma prekallikrein, the serine protease zymogen that releases vasoactive bradykinin; target of in vivo CRISPR and ASO therapies for hereditary angioedema.
Approved Symbol
KLKB1
Chromosomal Locus
4q35.2
Encoded Product
Plasma prekallikrein zymogen (619 mature aa) cleaved by Factor XIIa into active Plasma Kallikrein (EC 3.4.21.34)
Primary Pathway
Contact activation system & high-molecular-weight kininogen cleavage to bradykinin
Clinical / Therapeutic Role
Deficiency causes benign Fletcher trait; target of NTLA-2002 CRISPR knockout, donidalorsen ASO & lanadelumab for Hereditary Angioedema
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 15-exon gene on chromosome 4q35.2 positioned adjacent to coagulation factor XI (F11), encoding an 85–88 kDa glycoprotein with four N-terminal apple domains (A1–A4, which bind high-molecular-weight kininogen) linked by a disulfide bond to a C-terminal trypsin-like serine protease catalytic domain.
Cellular & Tissue Expression Profile: Synthesized and secreted into plasma almost exclusively by hepatic hepatocytes, circulating ~75–80% non-covalently complexed with high-molecular-weight kininogen (HMWK, encoded by KNG1).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Upon reciprocal contact activation with Factor XIIa (FXIIa), single-chain prekallikrein is cleaved at Arg371-Ile372 into two-chain active plasma kallikrein, which both amplifies FXII activation and cleaves HMWK to liberate the potent nonapeptide vasodilator bradykinin—increasing vascular endothelial permeability via B2 receptors (BDKRB2).
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: While hereditary angioedema (HAE) is caused by heterozygous deficiency of C1 esterase inhibitor (SERPING1)—permitting runaway plasma kallikrein activity and life-threatening laryngeal and visceral bradykinin-mediated edema—individuals with biallelic loss-of-function mutations in KLKB1 (Fletcher trait) have prolonged in vitro activated partial thromboplastin time (aPTT) yet suffer no bleeding tendency or clinical pathology.
Therapeutic & Clinical Pharmacology: Because KLKB1 is dispensable for normal hemostasis, it is an ideal therapeutic target in HAE: blocked in plasma by monoclonal antibody lanadelumab (Takhzyro) and oral berotralstat, silenced in hepatocytes by the GalNAc-ASO donidalorsen, and permanently knocked out by single-dose LNP-CRISPR-Cas9 therapy lonvoguran ziclumeran (NTLA-2002), which eliminates angioedema attacks in clinical trials.