Klotho (biology)

KL
Identifiers
AliasesKL, entrez:9365, klotho, HFTC3
External IDsOMIM: 604824 MGI: 1101771 HomoloGene: 68415 GeneCards: KL
Gene location (Human)
Chr.Chromosome 13 (human)[1]
Band13q13.1Start33,016,433 bp[1]
End33,066,145 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

9365

16591

Ensembl

ENSG00000133116

ENSMUSG00000058488

UniProt

Q9UEF7

O35082

RefSeq (mRNA)

NM_004795
NM_153683

NM_013823

RefSeq (protein)

NP_004786

NP_038851

Location (UCSC)Chr 13: 33.02 – 33.07 MbChr 5: 150.95 – 150.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Klotho is an enzyme that in humans is encoded by the KL gene.[5]

This gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.[6][7] Transgenic mice that overexpress Klotho live longer than wild-type mice.[8]

Function

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Kuro-o et al.[9] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[10][11] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[12]

The binding of certain fibroblast growth factors (FGF's) viz., FGF19, FGF20, and FGF23, to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho.[13][14]

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[8] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[15]

The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.[16] Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.[16] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).[17][18][19][20]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000133116 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000058488 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (Jan 1998). "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochemical and Biophysical Research Communications. 242 (3): 626–30. doi:10.1006/bbrc.1997.8019. PMID 9464267.
  6. ↑ "Entrez Gene: klotho".
  7. ↑ Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, et al. (2016). "KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference". Proceedings of the National Academy of Sciences of the United States of America. 113 (50): 14372–14377. doi:10.1073/pnas.1611243113. PMC 5167198. PMID 27911795.
  8. 1 2 Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (Sep 2005). "Suppression of aging in mice by the hormone Klotho". Science. 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. doi:10.1126/science.1112766. PMC 2536606. PMID 16123266.
  9. ↑ 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 YI (Nov 1997). "Mutation of the mouse klotho gene leads to a syndrome resembling ageing". Nature. 390 (6655): 45–51. Bibcode:1997Natur.390...45K. doi:10.1038/36285. PMID 9363890.
  10. ↑ Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (Jan 2002). "Association of human aging with a functional variant of klotho". Proceedings of the National Academy of Sciences of the United States of America. 99 (2): 856–61. Bibcode:2002PNAS...99..856A. doi:10.1073/pnas.022484299. PMC 117395. PMID 11792841.
  11. ↑ Rodriguez T (2015). "Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy". Journal of Molecular Biology Research. 5 (1): 11. doi:10.5539/jmbr.v5n1p11.
  12. ↑ Xiao NM, Zhang YM, Zheng Q, Gu J (May 2004). "Klotho is a serum factor related to human aging". Chinese Medical Journal. 117 (5): 742–7. PMID 15161545.
  13. ↑ Helsten T, Schwaederle M, Kurzrock R (2015). "Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications". Cancer Metastasis Reviews. 34 (3): 479–96. doi:10.1007/s10555-015-9579-8. PMC 4573649. PMID 26224133.
  14. ↑ Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA (February 2016). "FGF21 Regulates Sweet and Alcohol Preference". Cell Metabolism. 23 (2): 344–9. doi:10.1016/j.cmet.2015.12.008. PMC 4749404. PMID 26724861.
  15. ↑ Dena B. Dubal et al., Life Extension Factor Klotho Enhances Cognition, Cell Reports, 2014, DOI: 10.1016/j.celrep.2014.03.076 (open access)
  16. 1 2 Huang CL (May 2010). "Regulation of ion channels by secreted Klotho: mechanisms and implications". Kidney International. 77 (10): 855–60. doi:10.1038/ki.2010.73. PMID 20375979.
  17. ↑ Kuro-o M (Oct 2009). "Klotho and aging". Biochimica et Biophysica Acta. 1790 (10): 1049–58. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844.
  18. ↑ Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B (Aug 2008). "FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis". The Journal of Cell Biology. 182 (3): 459–65. doi:10.1083/jcb.200803024. PMC 2500132. PMID 18678710.
  19. ↑ Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (Dec 2003). "Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system". Molecular Endocrinology. 17 (12): 2393–403. doi:10.1210/me.2003-0048. PMID 14528024.
  20. ↑ Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y (Jun 2007). "alpha-Klotho as a regulator of calcium homeostasis". Science. 316 (5831): 1615–8. Bibcode:2007Sci...316.1615I. doi:10.1126/science.1135901. PMID 17569864.

Further reading

  • Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T (2009). "KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients". American Journal of Nephrology. 30 (4): 383–8. doi:10.1159/000235686. PMID 19690404.
  • Choi BH, Kim CG, Lim Y, Lee YH, Shin SY (Jan 2010). "Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1". Gene. 450 (1–2): 121–7. doi:10.1016/j.gene.2009.11.004. PMID 19913601.
  • Fukumoto S (Apr 2009). "[Chronic kidney disease (CKD) and bone. Regulation of calcium and phosphate metabolism by FGF23/Klotho]". Clinical Calcium. 19 (4): 523–8. PMID 19329831.
  • Nabeshima Y (Dec 2000). "Challenge of overcoming aging-related disorders". Journal of Dermatological Science. 24 Suppl 1: S15–21. doi:10.1016/S0923-1811(00)00136-5. PMID 11137391.
  • Razzaque MS (Mar 2009). "FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?". American Journal of Physiology. Renal Physiology. 296 (3): F470–6. doi:10.1152/ajprenal.90538.2008. PMC 2660189. PMID 19019915.
  • Menon R, Pearce B, Velez DR, Merialdi M, Williams SM, Fortunato SJ, Thorsen P (2009). "Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants". Reproductive Biology and Endocrinology. 7: 62. doi:10.1186/1477-7827-7-62. PMC 2714850. PMID 19527514.
  • Prié D, Ureña Torres P, Friedlander G (May 2009). "[Fibroblast Growth Factor 23-Klotho: a new axis of phosphate balance control]". Médecine Sciences. 25 (5): 489–95. doi:10.1051/medsci/2009255489. PMID 19480830.
  • Torres PU, Prié D, Beck L, De Brauwere D, Leroy C, Friedlander G (Jan 2009). "Klotho gene, phosphocalcic metabolism, and survival in dialysis". Journal of Renal Nutrition. 19 (1): 50–6. doi:10.1053/j.jrn.2008.10.018. PMID 19121771.
  • Halaschek-Wiener J, Amirabbasi-Beik M, Monfared N, Pieczyk M, Sailer C, Kollar A, Thomas R, Agalaridis G, Yamada S, Oliveira L, Collins JA, Meneilly G, Marra MA, Madden KM, Le ND, Connors JM, Brooks-Wilson AR (2009). Mary Bridger J, ed. "Genetic variation in healthy oldest-old". PLOS ONE. 4 (8): e6641. Bibcode:2009PLoSO...4.6641H. doi:10.1371/journal.pone.0006641. PMC 2722017. PMID 19680556.
  • Shimoyama Y, Nishio K, Hamajima N, Niwa T (Aug 2009). "KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism, bone mineral density and systolic blood pressure in Japanese healthy subjects". Clinica Chimica Acta; International Journal of Clinical Chemistry. 406 (1–2): 134–8. doi:10.1016/j.cca.2009.06.011. PMID 19539617.
  • Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H (Mar 2010). "A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population". Clinica Chimica Acta; International Journal of Clinical Chemistry. 411 (5–6): 386–90. doi:10.1016/j.cca.2009.12.004. PMID 20005218.
  • Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM (Dec 2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men". Journal of Bone and Mineral Research. 24 (12): 2039–49. doi:10.1359/jbmr.090524. PMC 2791518. PMID 19453261.
  • Torres PU, Prié D, Molina-Blétry V, Beck L, Silve C, Friedlander G (Apr 2007). "Klotho: an antiaging protein involved in mineral and vitamin D metabolism". Kidney International. 71 (8): 730–7. doi:10.1038/sj.ki.5002163. PMID 17332731.
  • Kurosu H, Kuro-o M (Jul 2008). "The Klotho gene family and the endocrine fibroblast growth factors". Current Opinion in Nephrology and Hypertension. 17 (4): 368–72. doi:10.1097/MNH.0b013e3282ffd994. PMID 18660672.
  • Kuro-o M (Oct 2009). "Klotho and aging". Biochimica et Biophysica Acta. 1790 (10): 1049–58. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844.
  • Wolf I, Laitman Y, Rubinek T, Abramovitz L, Novikov I, Beeri R, Kuro-O M, Koeffler HP, Catane R, Freedman LS, Levy-Lahad E, Karlan BY, Friedman E, Kaufman B (Jan 2010). "Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin". Oncogene. 29 (1): 26–33. doi:10.1038/onc.2009.301. PMID 19802015.
  • Invidia L, Salvioli S, Altilia S, Pierini M, Panourgia MP, Monti D, De Rango F, Passarino G, Franceschi C (Feb 2010). "The frequency of Klotho KL-VS polymorphism in a large Italian population, from young subjects to centenarians, suggests the presence of specific time windows for its effect". Biogerontology. 11 (1): 67–73. doi:10.1007/s10522-009-9229-z. PMID 19421891.
  • Nabeshima Y (Jul 2008). "[Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]". Clinical Calcium. 18 (7): 923–34. PMID 18591743.
  • Chen SN, Cilingiroglu M, Todd J, Lombardi R, Willerson JT, Gotto AM, Ballantyne CM, Marian AJ (2009). "Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis". BMC Medical Genetics. 10: 111. doi:10.1186/1471-2350-10-111. PMC 2775733. PMID 19878569.
  • Zhang R, Zheng F (Sep 2008). "PPAR-gamma and aging: one link through klotho?". Kidney International. 74 (6): 702–4. doi:10.1038/ki.2008.382. PMID 18756295.

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