Alternative titles; symbols
HGNC Approved Gene Symbol: KLKB1
SNOMEDCT: 48976006;
Cytogenetic location: 4q35.2 Genomic coordinates (GRCh38): 4:186,210,853-186,258,471 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q35.2 | Fletcher factor (prekallikrein) deficiency | 612423 | Autosomal recessive | 3 |
Chung et al. (1986) cloned a KLKB1 cDNA from a human liver cDNA library. Analysis of the cDNA indicated that plasma prekallikrein is synthesized as a precursor with a signal peptide of 19 amino acids. The mature form of the protein that circulates in blood is a single-chain polypeptide of 619 amino acids. Plasma prekallikrein is converted to plasma kallikrein by factor XIIa (610619) by the cleavage of an internal arg-ile bond. Plasma kallikrein is composed of a heavy chain (371 amino acids) and a light chain (248 amino acids), which are held together by a disulfide bond. The heavy chain originates from the N-terminal end of the zymogen and contains 4 tandem repeats (apple domains) that contain 90 or 91 amino acids. The light chain of plasma kallikrein contains the catalytic portion of the enzyme and is homologous to the trypsin family of serine proteases. Prekallikrein and factor XI (264900) share 58% amino acid sequence identity.
Wuepper (1973) and Weiss et al. (1974) presented evidence indicating identity of Fletcher factor (Hathaway et al., 1965) and prekallikrein.
Beaubien et al. (1991) demonstrated that, like the F11 gene, the KLKB1 gene contains 15 exons. Beaubien et al. (1991) also demonstrated that the gene organization of the catalytic subunit of KLKB1 is similar to that of trypsin and other related serine proteases. The findings suggested that plasma kallikrein and factor XI were derived from a common ancestor through gene duplication.
By in situ hybridization, Beaubien et al. (1991) mapped the KLKB1 gene to chromosome 4q35, where the F11 gene is located, and the mouse homolog to chromosome 8.
Tait and Fujikawa (1986) demonstrated that the kallikrein apple domains (A1 to A4) mediate the high affinity binding of the enzyme to its major substrate, high molecular weight kininogen (see 612358). Herwald et al. (1996) showed that the kallikrein-kininogen complex binds to cell surface receptors leading to the targeted action of bradykinin, the product of kallikrein-mediated proteolysis.
Prekallikrein Deficiency
In a 79-year-old Caucasian male with prekallikrein (Fletcher factor) deficiency (PKKD; 612423), Wynne Jones et al. (2004) identified a homozygous arg94-to-ter substitution in the KLKB1 gene (R94X; 229000.0001).
In a boy with extremely low prekallikrein activity and antigen, Lombardi et al. (2003) identified compound heterozygosity for 2 missense mutations in the KLKB1 gene (W383X, 229000.0002; C529Y, 229000.0003). The mutations segregated with the disorder in the family.
In a 60-year-old Indian man with PKKD, Abraham et al. (2022) identified a 1-bp duplication in the KLKB1 gene (c.451dupT; 229000.0006), which was originally identified by Maak et al. (2009).
Associations Pending Confirmation
In a study of 591 African Americans with end-stage renal disease (ESRD) and 139 African American control subjects, Yu et al. (2000) identified 12 allelic variants in the 5-prime proximal promoter and 7 exons of the KLKB1 gene. One common polymorphism present in 30% of the study population at position 521 of KLKB1 cDNA leads to the replacement of asparagine with serine at codon 124 in the heavy chain of the A2 domain of the protein. Several polymorphisms were found at a slightly increased frequency among families with end-stage renal disease; however, none of these associations was statistically significant. Yu et al. (2000) found an association of certain alleles of 2 CA/GT repeat polymorphic markers with ESRD in African Americans, but no causative mutation was identified.
For a history of the Fletcher factor, see 612423 and Giangrande (2003).
In a 79-year-old Caucasian male with prekallikrein deficiency (612423) whose parents were first cousins, Wynne Jones et al. (2004) identified a homozygous 430C-T transition in exon 5 of the KLKB1 gene, resulting in an arg94-to-ter (R94X) substitution. The patient presented with a 6-month history of stable exertional angina but otherwise had no significant past medical history. Coronary angiography and coronary artery bypass grafting were not complicated by abnormal bleeding; however, he had prolongation of the activated partial thromboplastin time (aPTT). Five heterozygous offspring of the proband each showed a normal aPTT but reduced prekallikrein activity and antigen. This was the first description of a kindred in which absence of expression of one or both KLKB1 alleles was confirmed by genotype.
In a boy with extremely low prekallikrein activity and antigen (612423), Lombardi et al. (2003) identified compound heterozygosity for 2 mutations in the KLKB1 gene: a 1298G-A transition in exon 11, resulting in a trp383-to-ter (W383X) substitution, and a 1736G-A transition in exon 14, resulting in a cys529-to-tyr (C529Y) substitution (229000.0003). He inherited the former mutation from his father and the latter mutation from his mother. The mutation was not found in 40 control subjects from the same geographic area. No associated abnormality was apparent in the proband or his parents.
For discussion of the cys529-to-tyr (C529Y) mutation in the KLKB1 gene that was found in compound heterozygous state in a patient with extremely low prekallikrein activity and antigen (612423) by Lombardi et al. (2003), see 229000.0002.
In 3 members of a Japanese family with plasma prekallikrein deficiency (612423), Katsuda et al. (2007) identified homozygosity for 2 mutations in exon 5 of the KLKB1 gene: a 438G-A transition resulting in a gly104-to-arg (G104R) substitution, and a 499A-G transition resulting in an asn124-to-ser (N124S) substitution (229000.0005). Both substitutions occurred in the A2 domain of the heavy chain. The authors designated this mutation PKD Seki. Using mutant A2 proteins in E. coli, Katsuda et al. (2007) demonstrated that the 2 substitutions in the A2 domain reduce the binding activity of A2 to high molecular weight kininogen, suggesting that this binding may play a crucial role in the first step of blood coagulation.
For discussion of the asn124-to-ser (N124S) mutation in the KLKB1 gene that was found in compound heterozygous state in patients with plasma prekallikrein deficiency (612423) by Katsuda et al. (2007), see 229000.0004.
In a 60-year-old man from India with asymptomatic prekallikrein deficiency (PKKD; 612423), Abraham et al. (2022) identified a homozygous 1-bp deletion in exon 5 of the KLKB1 gene (c.451dupT), which they designated c.444_445insT (chr4.186236896_186236897insT), resulting in a frameshift and premature termination (Ser151PhefsTer34). The authors stated that the mutation was originally reported by Maak et al. (2009) in a patient with severe PKKD.
Adenaeuer et al. (2021) analyzed the frequency of the c.451dupT mutation. Among 5 patients with PKKD who were homozygous for this mutation, 2 were African, 1 was African American, 1 was from Oman, and 1 was of unknown origin. Among 300 healthy Nigerian persons, this variant was found in 7/600 alleles (1.17%), suggesting a prevalence of PKKD of about 1:7000 in Nigeria.
Abraham, R. M., Viswanathan, G. K., Dass, J., Dhawan, R., Aggarwal, M., Kumar, P., Seth, T., Mahapatra, M. Prekallikrein deficiency due to homozygous KLKB1(+) mutation c.444_445insT (p.Ser151PhefsTer34). (Letter) Int. J. Lab. Hemat. 44: e132-e134, 2022. [PubMed: 34847617] [Full Text: https://doi.org/10.1111/ijlh.13773]
Adenaeuer, A., Ezigbo, E. D., Fawzy Nazir, H., Barco, S., Trinchero, A., Laubert-Reh, D., Strauch, K., Wild, P. S., Lackner, K. J., Lammle, B., Rossmann, H. c.451dupT in KLKB1 is common in Nigerians, confirming a higher prevalence of severe prekallikrein deficiency in Africans compared to Europeans. J. Thromb. Haemost. 19: 147-152, 2021. [PubMed: 33073460] [Full Text: https://doi.org/10.1111/jth.15137]
Beaubien, G., Rosinski-Chupin, I., Mattei, M. G., Mbikay, M., Chretien, M., Seidah, N. G. Gene structure and chromosomal localization of plasma kallikrein. Biochemistry 30: 1628-1635, 1991. [PubMed: 1993180] [Full Text: https://doi.org/10.1021/bi00220a027]
Chung, D. W., Fujikawa, K., McMullen, B. A., Davie, E. W. Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats. Biochemistry 25: 2410-2417, 1986. [PubMed: 3521732] [Full Text: https://doi.org/10.1021/bi00357a017]
Giangrande, P. L. F. Historical review: six characters in search of an author: the history of the nomenclature of coagulation factors. Brit. J. Haemat. 121: 703-712, 2003. [PubMed: 12780784] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04333.x]
Hathaway, W. E., Alsever, J. The relation of 'Fletcher factor' to factor XI and XII. Brit. J. Haemat. 18: 161-169, 1970. [PubMed: 5439523] [Full Text: https://doi.org/10.1111/j.1365-2141.1970.tb01431.x]
Hathaway, W. E., Belhasen, L. P., Hathaway, H. S. Evidence for a new plasma thromboplastin factor. I. Case report, coagulation studies and physiochemical properties. Blood 26: 521-532, 1965. [PubMed: 5845778]
Herwald, H., Dedio, J., Kellner, R., Loos, M., Muller-Esterl, W. Isolation and characterization of the kininogen-binding protein p33 from endothelial cells: identity with the gC1q receptor J. Biol. Chem. 271: 13040-13047, 1996. [PubMed: 8662673] [Full Text: https://doi.org/10.1074/jbc.271.22.13040]
Katsuda, I., Maruyama, F., Ezaki, K., Sawamura, T., Ichihara, Y. A new type of plasma prekallikrein deficiency associated with homozygosity for gly104arg and asn124ser in apple domain 2 of the heavy-chain region. Europ. J. Haemat. 79: 59-68, 2007. Note: Erratum: Europ J. Haemat. 79: 185 only, 2007. [PubMed: 17598838] [Full Text: https://doi.org/10.1111/j.1600-0609.2007.00871.x]
Lombardi, A. M., Sartori, M. T., Cabrio, L. Fadin, M., Zanon, E., Girolami, A. Severe prekallikrein (Fletcher factor) deficiency due to a compound heterozygosis (383trp stop codon and cys529tyr). Thromb. Haemost. 90: 1040-1045, 2003. [PubMed: 14652634] [Full Text: https://doi.org/10.1160/TH03-05-0275]
Maak, B., Kochhan, L., Heuchel, P., Jenderny, J. Severe prekallikrein deficiency due to a compound heterozygosis in the KLKB1 gene. Hamostaseologie 29: 187-189, 2009. Note: Article in German. [PubMed: 19404525]
Saito, H., Ratnoff, O. D., Donaldson, V. H., Abilgaard, C. C., Hattersley, P. G. Fletcher factor. (Letter) Blood 39: 745-747, 1972.
Tait, J. F., Fujikawa, K. Identification of the binding site for plasma prekallikrein in human high molecular weight kininogen: a region from residues 185 to 224 of the kininogen light chain retains full binding activity. J. Biol. Chem. 261: 15396-15401, 1986. [PubMed: 3096985]
Weiss, A. S., Gallin, J. I., Kaplan, A. Fletcher factor deficiency: a diminished rate of Hageman factor activation caused by absence of prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic activity, and kinin generation. J. Clin. Invest. 53: 622-633, 1974. [PubMed: 11344577] [Full Text: https://doi.org/10.1172/JCI107597]
Wuepper, K. D. Prekallikrein deficiency in man. J. Exp. Med. 138: 1345-1355, 1973. [PubMed: 4762550] [Full Text: https://doi.org/10.1084/jem.138.6.1345]
Wynne Jones, D., Russell, G., Allford, S. L., Burdon, K., Hawkins, G. A., Bowden, D. W., Minaee, S., Mumford, A. D. Severe prekallikrein deficiency associated with homozygosity for an arg94stop nonsense mutation. Brit. J. Haemat. 127: 220-223, 2004. [PubMed: 15461630] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.05180.x]
Yu, H., Anderson, P. J., Freedman, B. I., Rich, S. S., Bowden, D. W. Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease. Genomics 69: 225-234, 2000. [PubMed: 11031105] [Full Text: https://doi.org/10.1006/geno.2000.6330]