Klotho (biology)

Klotho
Identifiers
Symbol	KL
External IDs	OMIM: 604824 MGI: 1101771 HomoloGene: 68415 GeneCards: KL Gene
EC number	3.2.1.31
Gene ontology Molecular function • beta-glucuronidase activity • signal transducer activity • fibroblast growth factor receptor binding • hormone activity • vitamin D binding • beta-glucosidase activity • fibroblast growth factor binding Cellular component • extracellular region • extracellular space • intracellular • plasma membrane • integral component of plasma membrane • integral component of membrane • extracellular exosome Biological process • acute inflammatory response • carbohydrate metabolic process • energy reserve metabolic process • epidermal growth factor receptor signaling pathway • aging • insulin receptor signaling pathway • fibroblast growth factor receptor signaling pathway • positive regulation of bone mineralization • Fc-epsilon receptor signaling pathway • innate immune response • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • calcium ion homeostasis • positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9365	16591
Ensembl	ENSG00000133116	ENSMUSG00000058488
UniProt	Q9UEF7	O35082
RefSeq (mRNA)	NM_004795	NM_013823
RefSeq (protein)	NP_004786	NP_038851
Location (UCSC)	Chr 13: 33.02 – 33.07 Mb	Chr 5: 150.95 – 150.99 Mb
PubMed search

Klotho is an enzyme that in humans is encoded by the KL gene.^[1]

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 and bone loss.^[2] Transgenic mice that overexpress Klotho live longer than wild-type mice.^[3]

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 aging. Its discovery was documented in 1997 by Kuro-o et al.^[4] 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,^[5][6] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.^[7]

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.^[3] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.^[8]

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.^[9] Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.^[9] 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).^{[10][11][12][13]}

References

1. 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.
2. "Entrez Gene: klotho".
3. 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.
4. 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.
5. 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.
6. Rodriguez, T. (2015). Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy. Journal of Molecular Biology Research, 5(1), p11.
7. 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.
8. Dena B. Dubal et al., Life Extension Factor Klotho Enhances Cognition, Cell Reports, 2014, DOI: 10.1016/j.celrep.2014.03.076 (open access)
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.

External links

• Entrez Gene entry for Klotho
• GenAge entry for Klotho

This article incorporates text from the United States National Library of Medicine, which is in the public domain.