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

• There were no Klotho-related differences in height, body weight, calcium intake, tobacco or alcohol consumption, or serum testosterone levels [6].

High impact information on KL

• Klotho-induced insulin resistance: a blessing in disguise [7]?
• A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes [1].
• KLOTHO allele status and the risk of early-onset occult coronary artery disease [8].
• We previously identified a functional variant of KLOTHO (termed "KL-VS"), which harbors two amino acid substitutions in complete linkage disequilibrium and is associated with reduced human longevity when in homozygosity [8].
• Klotho-deficient mice display extensive arteriosclerosis when fed a normal diet, suggesting a potent genetic predisposition [8].

Chemical compound and disease context of KL

• BACKGROUND: Recently, klotho has been proposed as a link between cardiovascular diseases and premature aging, but the relationship between KLOTHO genes and cardiovascular risk factors, especially glucose metabolism, in humans is unclear [9].

Biological context of KL

• The klotho mouse, which genetically lacks klotho gene expression, manifests various systemic phenotypes resembling aging [10].
• In conclusion, we describe the primary structure and gene expression of a novel protein related to klotho protein [10].
• In a transient transfection assay, secreted levels of klotho harboring V352 are reduced 6-fold, whereas extracellular levels of the S370 form are increased 2.9-fold [11].
• To determine whether variation in the human KLOTHO locus contributes to survival, we applied two newly characterized polymorphic microsatellite markers flanking the gene in a population-based association study [11].
• An initial screen and follow-up studies showed that individual SNPs and haplotypes composed of several SNPs in bone morphogenic protein 6, annexin A2, and klotho were associated with sickle cell osteonecrosis [2].

Anatomical context of KL

• These data suggest that variation in the KL gene product affects osteoblast activity independent of osteoclast activity but that this defect does not result in an effect on bone structure in this population, perhaps because of "rescue" by other genetic or environmental factors in this population [12].
• Klotho stabilizes the TRPV5 Ca2+ channel in the plasma membrane by deglycosylation of the protein [13].
• Using the ELISA system, we detected the human Klotho protein as low as 20 ng/ml in the supernatant of Chinese hamster ovary cells (CHO cells), introduced the human klotho gene [14].
• Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells [15].
• Klotho overexpression decreased H(2)O(2)-induced apoptosis in COS-1 cells and Jurkat cells [15].

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

• KL directly or indirectly promotes endothelial nitric oxide (NO) production and the TEK receptor tyrosine kinase is involved in angiogenesis [19].
• Downregulation of Klotho dramatically induces premature senescence with a concomitant upregulation of p21 [20].
• These results demonstrate that Klotho normally regulates cellular senescence by repressing the p53/p21 pathway [20].

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].

References