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Gene Review

KL  -  klotho

Homo sapiens

Synonyms: Klotho
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Disease relevance of KL

  • A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema [1].
  • Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis [2].
  • These findings indicate that the klotho gene may be a candidate for the genetic regulation of common age-related diseases like osteoporosis and spondylosis, and we provide the first evidence suggesting that this gene may be involved in the etiology of human diseases [3].
  • Based on the fact that the klotho-deficient mouse exhibits multiple aging phenotypes, including osteopenia and subchondral sclerosis of joints, we explored the possibility of whether human klotho gene polymorphism is associated with two major age-related skeletal disorders: osteoporosis and spondylosis [3].
  • Severely reduced production of klotho in human chronic renal failure kidney [4].
  • Klotho mRNA levels were significantly decreased (n = 23) or undetectable (n = 17) in parathyroid adenomas compared to normal tissues (P < 0.001) [5].

Psychiatry related information on KL


High impact information on KL


Chemical compound and disease context of KL


Biological context of KL


Anatomical context of KL


Associations of KL with chemical compounds

  • The corresponding substitution, F289V, in the closest human klotho paralog with a known substrate, cBGL1, completely eliminates its ability to cleave p-nitrophenyl-beta-D-glucoside [11].
  • Amino acid sequence analysis indicates that human cytosolic beta-glycosidase is most closely related to lactase phlorizin hydrolase and klotho protein [16].
  • Klotho protein also reduced H(2)O(2)- and etoposide-induced apoptosis in HUVEC [15].
  • In this paper, we describe the present understanding of the concerted action of calbindin-D(28k), klotho and BSPRY (B-box and SPRY-domain-containing protein) at different levels throughout the epithelial cell to control Ca(2+) influx at the luminal entry gate [17].
  • Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity [18].

Regulatory relationships of KL


Other interactions of KL

  • Unlike klotho protein, it possesses neither a signal sequence nor a transmembrane domain, suggesting that it is a cytosolic protein, and thus was termed cytosolic beta-glucosidase-like protein-1 (cBGL1) [10].
  • The level of kl gene expression was measured by utilizing RNase protection assay [4].
  • The c-kit receptor and its cognate ligand, KL, play a critical role in melanogenesis, gametogenesis, and hematopoiesis [21].
  • These results suggest that AR is a susceptibility gene for reduced BMD in premenopausal Japanese women, and that KL is a susceptibility gene for reduced BMD in all women [22].
  • These findings may have broader implications in sickle cell disease, as KL encodes a membrane protein that regulates many vascular functions, including vascular endothelial growth factor expression and endothelial nitric oxide release [23].

Analytical, diagnostic and therapeutic context of KL

  • Molecular cloning and expression of a novel klotho-related protein [10].
  • To determine whether klotho influences atherosclerotic risk in humans, we performed cross-sectional studies to assess the association between the KL-VS allele and occult coronary artery disease (CAD) in two independent samples of apparently healthy siblings of individuals with early-onset (age <60 years) CAD (SIBS-I [N=520] and SIBS-II [N=436]) [8].
  • In Western blots, KM2076 and KM2119 specifically recognized a 130 kDa Klotho protein in the mouse and human kidney membrane fractions [14].
  • To detect the human Klotho protein, the sandwich-type ELISA system with KM2076 and KM2365 was established [14].
  • KM2076 and KM2119 specifically gave a positive staining by immunohistochemical staining in paraffin or frozen sections of the kidneys from wild-type mice but not in those from kl mice [14].


  1. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y.I. Nature (1997) [Pubmed]
  2. Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis. Baldwin, C., Nolan, V.G., Wyszynski, D.F., Ma, Q.L., Sebastiani, P., Embury, S.H., Bisbee, A., Farrell, J., Farrer, L., Steinberg, M.H. Blood (2005) [Pubmed]
  3. Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women. Ogata, N., Matsumura, Y., Shiraki, M., Kawano, K., Koshizuka, Y., Hosoi, T., Nakamura, K., Kuro-O, M., Kawaguchi, H. Bone (2002) [Pubmed]
  4. Severely reduced production of klotho in human chronic renal failure kidney. Koh, N., Fujimori, T., Nishiguchi, S., Tamori, A., Shiomi, S., Nakatani, T., Sugimura, K., Kishimoto, T., Kinoshita, S., Kuroki, T., Nabeshima , Y. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  5. Type I membrane klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism. Björklund, P., Krajisnik, T., Akerström, G., Westin, G., Larsson, T.E. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  6. Klotho gene polymorphism and male bone mass. Zarrabeitia, M.T., Hern??ndez, J.L., Valero, C., Zarrabeitia, A.L., Ortiz, F., Gonzalez-Macias, J., Riancho, J.A. Calcif. Tissue Int. (2007) [Pubmed]
  7. Klotho-induced insulin resistance: a blessing in disguise? Unger, R.H. Nat. Med. (2006) [Pubmed]
  8. KLOTHO allele status and the risk of early-onset occult coronary artery disease. Arking, D.E., Becker, D.M., Yanek, L.R., Fallin, D., Judge, D.P., Moy, T.F., Becker, L.C., Dietz, H.C. Am. J. Hum. Genet. (2003) [Pubmed]
  9. Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. Rhee, E.J., Oh, K.W., Yun, E.J., Jung, C.H., Lee, W.Y., Kim, S.W., Baek, K.H., Kang, M.I., Park, S.W. J. Endocrinol. Invest. (2006) [Pubmed]
  10. Molecular cloning and expression of a novel klotho-related protein. Yahata, K., Mori, K., Arai, H., Koide, S., Ogawa, Y., Mukoyama, M., Sugawara, A., Ozaki, S., Tanaka, I., Nabeshima, Y., Nakao, K. J. Mol. Med. (2000) [Pubmed]
  11. Association of human aging with a functional variant of klotho. Arking, D.E., Krebsova, A., Macek, M., Macek, M., Arking, A., Mian, I.S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H.C. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  12. Klotho gene polymorphisms are associated with osteocalcin levels but not bone density of aged postmenopausal women. Mullin, B.H., Wilson, S.G., Islam, F.M., Calautti, M., Dick, I.M., Devine, A., Prince, R.L. Calcif. Tissue Int. (2005) [Pubmed]
  13. Recent advances in renal tubular calcium reabsorption. Mensenkamp, A.R., Hoenderop, J.G., Bindels, R.J. Curr. Opin. Nephrol. Hypertens. (2006) [Pubmed]
  14. Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys. Kato, Y., Arakawa, E., Kinoshita, S., Shirai, A., Furuya, A., Yamano, K., Nakamura, K., Iida, A., Anazawa, H., Koh, N., Iwano, A., Imura, A., Fujimori, T., Kuro-o, M., Hanai, N., Takeshige, K., Nabeshima, Y. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  15. Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Ikushima, M., Rakugi, H., Ishikawa, K., Maekawa, Y., Yamamoto, K., Ohta, J., Chihara, Y., Kida, I., Ogihara, T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  16. Cloning and characterization of human liver cytosolic beta-glycosidase. de Graaf, M., van Veen, I.C., van der Meulen-Muileman, I.H., Gerritsen, W.R., Pinedo, H.M., Haisma, H.J. Biochem. J. (2001) [Pubmed]
  17. Concerted action of associated proteins in the regulation of TRPV5 and TRPV6. Schoeber, J.P., Hoenderop, J.G., Bindels, R.J. Biochem. Soc. Trans. (2007) [Pubmed]
  18. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Arking, D.E., Atzmon, G., Arking, A., Barzilai, N., Dietz, H.C. Circ. Res. (2005) [Pubmed]
  19. Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Nolan, V.G., Adewoye, A., Baldwin, C., Wang, L., Ma, Q., Wyszynski, D.F., Farrell, J.J., Sebastiani, P., Farrer, L.A., Steinberg, M.H. Br. J. Haematol. (2006) [Pubmed]
  20. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. de Oliveira, R.M. FEBS Lett. (2006) [Pubmed]
  21. Expression of c-kit and kit ligand proteins in normal human tissues. Lammie, A., Drobnjak, M., Gerald, W., Saad, A., Cote, R., Cordon-Cardo, C. J. Histochem. Cytochem. (1994) [Pubmed]
  22. Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women. Yamada, Y., Ando, F., Niino, N., Shimokata, H. J. Mol. Med. (2005) [Pubmed]
  23. Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Nolan, V.G., Baldwin, C., Ma, Q., Wyszynski, D.F., Amirault, Y., Farrell, J.J., Bisbee, A., Embury, S.H., Farrer, L.A., Steinberg, M.H. Br. J. Haematol. (2005) [Pubmed]
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