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Gene Review

Kl  -  klotho

Mus musculus

Synonyms: Klotho, alpha-kl
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Disease relevance of Kl

  • Klotho gene mutant mice (klotho mice, also called kl/kl) exhibit osteopetrosis in the metaphysis of femora and tibiae and die within 3 months [1].
  • Klotho mutant mouse (kl-/-), a mouse model for human aging, exhibits various phenotypes in a wide range of organs including arteriosclerosis, neural degeneration, skin and gonadal atrophy, pulmonary emphysema, calcification of soft tissues, and cognition impairment [2].
  • In the present study, we analyzed the gene expression of plasminogen activator inhibitor-1 (PAI-1), a key molecule in the development of thrombosis, in a murine model of aging, klotho mutant ( kl/kl) mice [3].
  • We propose the contribution of an aging-suppressing gene, klotho, as a novel systemic factor, as a mouse deficient in the klotho gene exhibits multiple aging phenotypes including osteopenia with a low bone turnover [4].
  • Klotho protein deficiency leads to overactivation of mu-calpain [5].

High impact information on Kl


Biological context of Kl

  • Because Klotho induces IGF-1 and insulin resistance, these findings appear to contradict previous evidence for increased life span of dwarf mice with reduced IGF-1 and insulin levels and enhanced insulin sensitivity [9].
  • These findings suggest that this deterioration in the vitamin D endocrine system may result in many of the phenotypes in kl-/- mice through effects of increased levels of calcium and phosphorus and 1,25-(OH)2D [10].
  • Klotho protein may participate in calcium and phosphorus homeostasis via the regulation of the 1,25-(OH)2D signaling pathway [10].
  • Furthermore, the normal genetic responses to administered 1,25-(OH)2D3, such as down-regulation of the 25-hydroxyvitamin D 1alpha-hydroxylase gene and up-regulation of 24-hydroxylase and VDR genes, were apparently impaired in kl-/- mice [10].
  • Therefore, the pathway downstream after generation of second messengers following stimulation of PTH (such as the sorting of transporters of Ca absorption) might be impaired by disruption of the Klotho gene [11].

Anatomical context of Kl


Associations of Kl with chemical compounds


Physical interactions of Kl

  • Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span [14].

Regulatory relationships of Kl

  • Our findings suggest that the klotho gene inhibited the differentiation of the granular duct from the striated duct due to the repression and/or down-regulation of sexual and growth hormones [15].

Other interactions of Kl

  • Single heterozygous mutation in the opg gene locus alone (without klotho mutation) did not show phenotype (trabecular bone volume, 5.84%; not significantly different from wild type) [1].
  • Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein [16].
  • Serum concentrations of calcitonin and PTH of kl-/- mice were normally up- and down-regulated, respectively, in response to the high levels of calcium [10].
  • Feeding of a low-P(i) diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice [17].
  • Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, "Klotho" mouse [3].

Analytical, diagnostic and therapeutic context of Kl


  1. Double mutations in klotho and osteoprotegerin gene loci rescued osteopetrotic phenotype. Yamashita, T., Okada, S., Higashio, K., Nabeshima, Y., Noda, M. Endocrinology (2002) [Pubmed]
  2. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Li, S.A., Watanabe, M., Yamada, H., Nagai, A., Kinuta, M., Takei, K. Cell Struct. Funct. (2004) [Pubmed]
  3. Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, "Klotho" mouse. Takeshita, K., Yamamoto, K., Ito, M., Kondo, T., Matsushita, T., Hirai, M., Kojima, T., Nishimura, M., Nabeshima, Y., Loskutoff, D.J., Saito, H., Murohara, T. Semin. Thromb. Hemost. (2002) [Pubmed]
  4. Molecular backgrounds of age-related osteoporosis from mouse genetics approaches. Kawaguchi, H. Reviews in endocrine & metabolic disorders (2006) [Pubmed]
  5. Klotho protein deficiency leads to overactivation of mu-calpain. Manya, H., Inomata, M., Fujimori, T., Dohmae, N., Sato, Y., Takio, K., Nabeshima, Y., Endo, T. J. Biol. Chem. (2002) [Pubmed]
  6. Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. Ito, S., Fujimori, T., Furuya, A., Satoh, J., Nabeshima, Y., Nabeshima, Y. J. Clin. Invest. (2005) [Pubmed]
  7. Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. Kawaguchi, H., Manabe, N., Miyaura, C., Chikuda, H., Nakamura, K., Kuro-o, M. J. Clin. Invest. (1999) [Pubmed]
  8. Aging mechanisms. Takahashi, Y., Kuro-O, M., Ishikawa, F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  9. Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging. Bartke, A. Trends Endocrinol. Metab. (2006) [Pubmed]
  10. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Yoshida, T., Fujimori, T., Nabeshima, Y. Endocrinology (2002) [Pubmed]
  11. Defect in parathyroid-hormone-induced luminal calcium absorption in connecting tubules of Klotho mice. Tsuruoka, S., Nishiki, K., Ioka, T., Ando, H., Saito, Y., Kurabayashi, M., Nagai, R., Fujimura, A. Nephrol. Dial. Transplant. (2006) [Pubmed]
  12. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. Nagai, T., Yamada, K., Kim, H.C., Kim, Y.S., Noda, Y., Imura, A., Nabeshima, Y., Nabeshima, T. FASEB J. (2003) [Pubmed]
  13. Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. Tohyama, O., Imura, A., Iwano, A., Freund, J.N., Henrissat, B., Fujimori, T., Nabeshima, Y. J. Biol. Chem. (2004) [Pubmed]
  14. Suppression of aging in mice by the hormone Klotho. Kurosu, H., Yamamoto, M., Clark, J.D., Pastor, J.V., Nandi, A., Gurnani, P., McGuinness, O.P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., Shimomura, I., Takayama, Y., Herz, J., Kahn, C.R., Rosenblatt, K.P., Kuro-o, M. Science (2005) [Pubmed]
  15. Histological and immunohistochemical changes in the submandibular gland in klotho-deficient mice. Suzuki, H., Amizuka, N., Noda, M., Amano, O., Maeda, T. Arch. Histol. Cytol. (2006) [Pubmed]
  16. Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Ito, S., Kinoshita, S., Shiraishi, N., Nakagawa, S., Sekine, S., Fujimori, T., Nabeshima, Y.I. Mech. Dev. (2000) [Pubmed]
  17. Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice. Segawa, H., Yamanaka, S., Ohno, Y., Onitsuka, A., Shiozawa, K., Aranami, F., Furutani, J., Tomoe, Y., Ito, M., Kuwahata, M., Imura, A., Nabeshima, Y., Miyamoto, K. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  18. Impaired regulation of gonadotropins leads to the atrophy of the female reproductive system in klotho-deficient mice. Toyama, R., Fujimori, T., Nabeshima, Y., Itoh, Y., Tsuji, Y., Osamura, R.Y., Nabeshima, Y. Endocrinology (2006) [Pubmed]
  19. Klotho reduces apoptosis in experimental ischaemic acute renal failure. Sugiura, H., Yoshida, T., Tsuchiya, K., Mitobe, M., Nishimura, S., Shirota, S., Akiba, T., Nihei, H. Nephrol. Dial. Transplant. (2005) [Pubmed]
  20. Regulation of angiogenesis by the aging suppressor gene klotho. Fukino, K., Suzuki, T., Saito, Y., Shindo, T., Amaki, T., Kurabayashi, M., Nagai, R. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
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