Alternative titles; symbols
HGNC Approved Gene Symbol: KLK1
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:50,819,146-50,823,787 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | [Kallikrein, decreased urinary activity of] | 615953 | 3 |
KLK1, or tissue kallikrein (EC 3.4.21.35), is a serine protease that generates Lys-bradykinin by specific proteolysis of kininogen-1 (KNG1; 612358) (Lundwall et al., 2006).
Gan et al. (2000) stated that the deduced 262-amino acid KLK1 protein contains a putative signal peptide, followed by a short activating peptide and the protease domain. The protease domain contains the catalytic triad of his65, asp120, and ser214. RT-PCR detected variable expression of KLK1 in most of the 35 tissues examined. Highest expression was in pancreas, salivary gland, thyroid, parotid gland, fetal and adult skin, kidney, and liver.
Gan et al. (2000) reported that the KLK1 gene contains 5 coding exons.
Evans et al. (1988) noted that, despite the variable number of genes encoding glandular kallikreins in mammalian species, in all species examined 1 particular kallikrein is functionally conserved in its capacity to release the vasoactive peptide, Lys-bradykinin, from low molecular mass kininogen. This kallikrein is found in kidney, pancreas, and salivary gland, showing a unique pattern of tissue-specific expression relative to other members of the family. Evans et al. (1988) isolated a genomic clone carrying the human renal kallikrein gene and localized it to human 19q13, most likely in the region q13.2-q13.4, by Southern analysis of hybrid cells and by in situ hybridization. In mouse, the corresponding gene is found on chromosome 7.
Richards et al. (1991) used a highly polymorphic microsatellite repeat sequence located 3-prime to the KLK1 gene to map it in relation to APOC2 (608083). They concluded that KLK1 is approximately 10 cM distal to APOC2 and that these markers flank the myotonic dystrophy gene.
By contour-clamped homogeneous electric field (CHEF) electrophoresis and chromosome walking, Riegman et al. (1992) showed clustering of the KLK1, APS (176820), and KLK2 (147960) genes. The KLK1 gene is positioned in the opposite orientation of the APS and KLK2 genes in the order KLK1--APS--KLK2. The APS and KLK2 genes are separated by 12 kb; the distance between KLK1 and APS is 31 kb. A CpG island was detected in the region between KLK1 and APS. Preliminary data indicated that this CpG island is located directly adjacent to a gene that is unrelated to the kallikreins and seems to be ubiquitously expressed.
Genomic blot analysis of human DNA using a human renal kallikrein cDNA probe gave only 3 distinct bands (Fukushima et al., 1985; Baker and Shine, 1985), indicating that in man there are many fewer representatives of the kallikrein family than in rodents. However, Yousef and Diamandis (2000) showed that the kallikreins constitute a large multigene family in humans, similar to that in rodents. They defined a 300-kb human kallikrein gene region on chromosome 19q13.3-q13.4.
By sequencing the kallikrein gene cluster on chromosome 19q13, Gan et al. (2000) identified 13 kallikrein-related genes and 5 pseudogenes. KLK1 is the most centromeric gene in the cluster. Yousef et al. (2000) reported that the cluster contains at least 15 genes.
In a systematic search for molecular variants of the kallikrein gene, Slim et al. (2002) identified 9 SNPs, 5 of which were studied in hypertensive and normotensive individuals. None of the polymorphisms was associated with hypertension, but individuals heterozygous for an arg53-to-his polymorphism (R53H; 147910.0001) had a significant decrease in urinary kallikrein activity (615953).
Fujita et al. (2013) screened for promoter and coding region polymorphisms in the KLK1 gene in Japanese and found that 2 subjects who were homozygous for allele H (-130(G)11) had low urinary kallikrein activity. Urinary calcium and sodium excretions were larger in allele-H subjects than in non-allele-H subjects.
The term kallikrein, derived from the Greek 'kallikreas,' for pancreas, was coined by Kraut et al. (1930). Lundwall et al. (2006) noted that the term kallikrein has been used for decades to identify enzymes with kininogenase activity, but most of the enzymes in the extended kallikrein family are presumed not to have kininogenase activity. They provided a revised nomenclature in which kallikrein paralogs without proven kininogenase activity (i.e., KLK2 through KLK15) were called 'kallikrein-related peptidases.'
Low renal synthesis and urinary excretion of tissue kallikrein have repeatedly been linked to hypertension in animals and humans. Meneton et al. (2001) demonstrated that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro was decreased both under basal conditions and in response to beta-adrenergic stimulation. Furthermore, flow-induced vasodilatation was impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data showed that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggested that the kallikrein-kinin system may be involved in the development or progression of cardiovascular diseases.
Lund et al. (2006) presented evidence suggesting that kallikrein may play a role in the generation of plasmin from plasminogen (PLG; 173350). The authors observed that wound healing in Plat (173370)-null or Plau (191840)-null mice was similar to that in wildtype mice, but wound healing in mice deficient for both Plat and Plau was significantly delayed. These findings suggested functional overlap between these 2 plasminogen activators. However, wound healing in the Plat/Plau-deficient mice was not as impaired as in plasminogen-null mice, suggesting the presence of an additional plasminogen activator. Pharmacologic inhibition of kallikrein in Plat/Plau-null mice resulted in delayed wound healing similar to that in Plg-null mice. Lund et al. (2006) concluded that kallikrein may play a role in plasmin generation.
Evans and Richards (1985) reported that nerve growth factor isolated from the submaxillary gland of adult male mice is a high molecular weight hexamer composed of 2 subunits each of alpha, beta, and gamma polypeptides. Both the alpha and the gamma subunits show homology with glandular kallikreins, a subset of serine proteases. Gamma-Ngf shows the arginylesterase activity characteristic of kallikreins and is believed to cleave pro-beta-ngf at 2 or more sites to generate active growth factor. The alpha subunit shows no measurable enzymatic activity but its presence is apparently necessary for the formation of the stable hexameric high molecular weight (7S) complex. Lack of enzyme activity can be attributed, at least in part, to the deletion of 15 nucleotides in a highly conserved coding region that is normally involved in the activation of the serine proteases from their inactive zymogen form. Evans and Richards (1985) concluded that in the mouse the genes for alpha and gamma Ngf are contiguous, transcribed from the same DNA strand, and separated by 5.3 kb of intergenic DNA. These are located on mouse chromosome 7. Scott (2021) noted that it is now recognized that the previously described alpha and gamma nerve growth factors in mouse are most similar at the protein level to Klk1.
In individuals heterozygous for a 230G-A transition in exon 3 of the KLKR gene, resulting in an arg53-to-his (R53H) substitution, Slim et al. (2002) identified a significant decrease in urinary kallikrein activity compared to controls (615953). This polymorphism was significantly more common in Afro-Caribbean individuals. Analysis of recombinant kallikrein variants revealed a major decrease in enzyme activity when arg53 was replaced by histidine, and a model of kallikrein derived from crystallographic data suggested that arg53 is involved in substrate binding.
In a study of 30 R53R homozygous and 10 R53H heterozygous young normotensive white males, Azizi et al. (2005) observed a 50 to 60% reduction in urinary kallikrein activity in R53H individuals, but renal and hormonal adaptation to dietary changes in sodium and potassium were unaffected. However, in studies of brachial artery function, R53H individuals consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared to R53R individuals. Azizi et al. (2005) concluded that this partial genetic deficiency in kallikrein activity is associated with a form of arterial dysfunction involving inappropriate inward remodeling of the brachial artery despite a chronic increase in shear stress.
Azizi, M., Boutouyrie, P., Bissery, A., Agharazii, M., Verbeke, F., Stern, N., Bura-Riviere, A., Laurent, S., Alhenc-Gelas, F., Jeunemaitre, X. Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans. J. Clin. Invest. 115: 780-787, 2005. [PubMed: 15765151] [Full Text: https://doi.org/10.1172/JCI23669]
Baker, A. R., Shine, J. Human kidney kallikrein: cDNA cloning and sequence analysis. DNA 4: 445-450, 1985. [PubMed: 3853975] [Full Text: https://doi.org/10.1089/dna.1985.4.445]
Evans, B. A., Richards, R. I. Genes for the alpha and gamma subunits of mouse nerve growth factor are contiguous. EMBO J. 4: 133-138, 1985. [PubMed: 3848399] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb02327.x]
Evans, B. A., Yun, Z. X., Close, J. A., Tregear, G. W., Kitamura, N., Nakanishi, S., Callen, D. F., Baker, E., Hyland, V. J., Sutherland, G. R., Richards, R. I. Structure and chromosomal localization of the human renal kallikrein gene. Biochemistry 27: 3124-3129, 1988. [PubMed: 2898948] [Full Text: https://doi.org/10.1021/bi00409a003]
Fujita, T., Yasuda, S., Kamata, M., Kamata, Y., Kumagai, Y., Majima, M. A common polymorphism in the tissue kallikrein gene is associated with increased urinary excretions of calcium and sodium in Japanese volunteers. J. Hum. Genet. 58: 758-761, 2013. [PubMed: 24005896] [Full Text: https://doi.org/10.1038/jhg.2013.93]
Fukushima, D., Kitamura, N., Nakanishi, S. Nucleotide sequence of cloned cDNA for human pancreatic kallikrein. Biochemistry 24: 8037-8043, 1985. [PubMed: 3004571] [Full Text: https://doi.org/10.1021/bi00348a030]
Gan, L., Lee, I., Smith, R., Argonza-Barrett, R., Lei, H., McCuaig, J., Moss, P., Paeper, B., Wang, K. Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region. Gene 257: 119-130, 2000. [PubMed: 11054574] [Full Text: https://doi.org/10.1016/s0378-1119(00)00382-6]
Kraut, H., Frey, E. K., Werle, E. Uber die Inaktivierung des Kallikreins. (VI. Mitteilung uber dieses Kreislaufhormon). Hoppe Seylers Z. Physiol. Chemie. 192: 1-21, 1930.
Lund, L. R., Green, K. A., Stoop, A. A., Ploug, M., Almholt, K., Lilla, J., Nielsen, B. S., Christensen, I. J., Craik, C. S., Werb, Z., Dano, K., Romer, J. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J. 25: 2686-2697, 2006. [PubMed: 16763560] [Full Text: https://doi.org/10.1038/sj.emboj.7601173]
Lundwall, A., Band, V., Blaber, M., Clements, J. A., Courty, Y., Diamandis, E. P., Fritz, H., Lilja, H., Malm, J., Maltais, L. J., Olsson, A. Y., Petraki, C., Scorilas, A., Sotiropoulou, G., Stenman, U.-H., Stephan, C., Talieri, M., Yousef, G. M. A comprehensive nomenclature for serine proteases with homology to tissue kallikreins. Biol. Chem. 387: 637-641, 2006. [PubMed: 16800724] [Full Text: https://doi.org/10.1515/BC.2006.082]
Meneton, P., Bloch-Faure, M., Hagege, A. A., Ruetten, H., Huang, W., Bergaya, S., Ceiler, D., Gehring, D., Martins, I., Salmon, G., Boulanger, C. M., Nussberger, J., Crozatier, B., Gasc, J.-M., Heudes, D., Bruneval, P., Doetschman, T., Menard, J., Alhenc-Gelas, F. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proc. Nat. Acad. Sci. 98: 2634-2639, 2001. [PubMed: 11226291] [Full Text: https://doi.org/10.1073/pnas.051619598]
Richards, R. I., Holman, K., Shen, Y., Kozman, H., Harley, H., Brook, D., Shaw, D. Human glandular kallikrein genes: genetic and physical mapping of the KLK1 locus using a highly polymorphic microsatellite PCR marker. Genomics 11: 77-82, 1991. [PubMed: 1684954] [Full Text: https://doi.org/10.1016/0888-7543(91)90103-l]
Riegman, P. H. J., Vlietstra, R. J., Suurmeijer, L., Cleutjens, C. B. J. M., Trapman, J. Characterization of the human kallikrein locus. Genomics 14: 6-11, 1992. [PubMed: 1385301] [Full Text: https://doi.org/10.1016/s0888-7543(05)80275-7]
Scott, A. F. Personal Communication. Baltimore, Md. 7/19/2021.
Slim, R., Torremocha, F., Moreau, T., Pizard, A., Hunt, S. C., Vuagnat, A., Williams, G. H., Gauthier, F., Jeunemaitre, X., Alhenc-Gelas, F. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J. Am. Soc. Nephrol. 13: 968-976, 2002. [PubMed: 11912256] [Full Text: https://doi.org/10.1681/ASN.V134968]
Yousef, G. M., Chang, A., Scorilas, A., Diamandis, E. P. Genomic organization of the human kallikrein gene family on chromosome 19q13.3-q13.4. Biochem. Biophys. Res. Commun. 276: 125-133, 2000. [PubMed: 11006094] [Full Text: https://doi.org/10.1006/bbrc.2000.3448]
Yousef, G. M., Diamandis, E. P. The expanded human kallikrein gene family: locus characterization and molecular cloning of a new member, KLK-L3 (KLK9). Genomics 65: 184-194, 2000. [PubMed: 10783266] [Full Text: https://doi.org/10.1006/geno.2000.6159]