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	[1]	[2]

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

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. Transgenic mice that overexpress Klotho live longer than wild-type mice.

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. 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, and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.

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

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. Additionally, klotho increases membrane expression of the inward rectifier channel ROMK. 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).

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.