The klotho gene encodes a single-pass membrane protein whose extracellular domain carries homology to beta-glucosidases. A defect in expression of klotho leads to syndromes resembling human aging in mice, including infertility (Kuro-o et al., 1997).FGF19 and FGF21 act through cell-surface receptors comprised of FGF receptors in complex with β-klotho, a transmembrane protein.
NCBI Summary:
This gene encodes a type-I membrane protein that is related to beta-glucosidases. 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. [provided by RefSeq, Jul 2008]
General function
Comment
Cellular localization
Secreted, Plasma membrane
Comment
Comparison of serum human Klotho levels and thiol/disulfide homeostasis in women with polycystic ovary syndrome and in healthy women. Biyik I et al. (2021) Women with polycystic ovary syndrome (PCOS) have an increased cardiometabolic risk. Similarly, it was previously shown that atherosclerotic and cardiovascular risk is increased in the general population with lower serum Klotho levels. The aim of this study was to investigate the lotho and thiol/disulfide levels in women with non-obese PCOS compared to healthy controls and also to investigate the relationship of serum Klotho and thiol/disulfide homeostasis with cardiometabolic risk factors. In this prospective case control study, human serum alpha Klotho levels and thiol/disulfide homeostasis of women with PCOS aged between 19-33 were compared to their age and BMI matched non - PCOS healthy controls. In addition, the correlation of these molecules with other metabolic markers/measurements were also investigated. Metabolic parameters such as mean waist circumference, lipid accumulation product, visceral adiposity index, fasting insulin, homeostasis model assessment of insulin resistance and triglyceride values were higher in the PCOS group (p = 0.038, p = 0.008, p = 0.001, p = 0.001, p = 0.002 and p = 0.002, respectively) compared to controls. However, mean serum Klotho and native thiol levels (respectively p < 0.0001 and p = 0.038) were lower compared to controls. Correlation analysis revealed that serum Klotho levels were negatively correlated with BMI, waist circumference, disulphide/total thiol, disulphide/native thiol, HOMA-IR and LAP-index. Findings of decreased serum Klotho and native thiol values of the PCOS group compared to controls and the negative correlation of serum Klotho levels with metabolic markers supports the idea that decreased Klotho may be another mechanism by which cardiovascular risk is increased in women with PCOS.////////////////// Serum β-Klotho concentrations are increased in women with polycystic ovary syndrome. Bednarska S et al. (2020) Polycystic ovary syndrome (PCOS) is a significant cause of menstrual disorders and infertility in women. The aim of this study was to evaluate the levels of Klotho expression in women with polycystic ovary syndrome. The study involved 67 patients with PCOS, as well as 18 controls. Serum levels of FGF19, FGF21 and β-Klotho were measured by ELISA technique. The blood samples were obtained between days 2 and 7 of menstrual cycle. The concentrations of β-Klotho, FGF19 and FGF21 were significantly increased in patients with PCOS; and appear to be statistically significant predictors of PCOS incidence. FGF19 (p = 0.031, OR = 1.01), exact β-Klotho levels (p = 0.022, OR = 1.01) and β-Klotho beyond the reference range (p = 0.008, OR = 4.66) were the most strongly correlated with the diagnosis of PCOS. In conclusion, FGF19, FGF21 and β-Klotho are increased in PCOS, and elevated β-Klotho concentration may become an useful diagnostic test for this disease. However, additional studies are required to further substantiate this observation.//////////////////
Ovarian function
Oocyte maturation
Comment
The effects of recombinant klotho in cisplatin-induced ovarian failure in mice. Biyik I et al. (2021) To investigate whether recombinant klotho given concomitantly with cisplatin is effective in preventing cisplatin-induced ovarian damage. Thirty-two adult female mice were divided into four groups. Saline was given to the first group, cisplatin to the second group, recombinant mouse klotho to the third group, and recombinant mouse klotho + cisplatin to the fourth group. The removed ovarian tissues were examined and groups were compared histologically and immunohistochemical examination for antimullerian hormone (AMH), superoxide dismutase (SOD) and catalase expression were done. Glutathione peroxidase (GPx) and glutathione reductase (GR) activities were measured by ELISA. Ovarian tissue weight, primary and secondary follicle counts were higher in cisplatin + recombinant klotho group compared to cisplatin group in our study (respectively p < 0.0001, p < 0.0001, and p = 0.010). Injury scores (stromal congestion, edema and infiltration, follicular degeneration scores and edema in corpus luteum scores) were similar between cisplatin and cisplatin + recombinant klotho groups (all p > 0.05). AMH staining intensities were similar between cisplatin and cisplatin + recombinant klotho groups (p = 0.925). There was no difference between the groups in terms of SOD, GPx, and GR (p > 0.05). The recombinant klotho administered before cisplatin could partially protect the ovarian tissue from cisplatin-induced ovarian damage considering that there was no difference in histologic injury score parameters, AMH staining intensity and oxidative stress markers between cisplatin and cisplatin plus klotho groups except that klotho preserved follicules to some extent. The antioxidant mechanism of action of klotho may not be the primary protection mechanism in cisplatin induced ovarian injury.////////////////// Effect of Klotho protein during porcine oocyte maturation via Wnt signaling. Kim EH et al. (2020) Klotho protein is well-known as an anti-aging agent, however, several studies have suggested that Klotho protein also increases antioxidant activity and the reproductive system, as Klotho protein is closely associated with Wnt signaling. The objective of our study was to investigate the enhancement of porcine oocyte in vitro maturation via the Klotho protein-Wnt signaling pathway. Following immunohistochemistry and ELISA, we treated cells with Klotho protein during in vitro maturation. Lithium Chloride, a specific activator of Wnt signaling, was subsequently co-administered with Klotho protein. Mature oocytes subjected to treatments were used for the analysis of embryonic development, qRT-PCR, and immunocytochemistry. Treatment with 5pg/ml Klotho protein significantly increased cumulus cell expansion, blastocyst formation rates, and the total cell number of blastocysts. During cotreatment with 5mM Lithium Chloride and 5pg/ml Klotho protein, blastocyst formation rates were the highest in Klotho protein-treated oocytes and the lowest in Lithium Chloride-treated oocytes. Expression levels of Wnt signaling-related transcripts and proteins were significantly impacted by Klotho protein and Lithium Chloride. Moreover, cellular ATP levels and antioxidant activities were enhanced by Klotho protein treatment. These findings suggest a significant involvement of the Klotho protein-Wnt signaling mechanism in porcine oocyte maturation.//////////////////
Abnormality of Klotho Signaling Is Involved in Polycystic Ovary Syndrome. Mao Z et al. (2017) This study investigated the involvement of the klotho-associated signaling in the apoptosis of granulosa cells (GCs) from the ovaries of patients with polycystic ovary syndrome (PCOS) and PCOS animals. Primary GCs were obtained from 26 healthy women and 43 women with PCOS. The PCOS animal model was established by the injection of dehydroepiandrosterone (DHEA). Klotho protein and associated microRNA expression in human primary GCs and rats' ovarian tissues were measured by Western blot and real-time polymerase chain reaction, respectively. Results showed that significantly lower miR-126-5p and miR-29a-5p microRNA expressions, higher klotho protein expression, lower insulin growth factor 1 (IGF-1R) and Wnt family member 1 (Wnt1) protein expressions, and lower Akt phosphorylation at Ser(473) and Thr(308) residues were observed in the GCs from patients with PCOS and the ovarian tissues of PCOS rats compared to that in GCs from healthy women and ovarian tissues of normal control rats, respectively. Knockdown of klotho gene expression normalized IGF-1R and Wnt1 protein expressions and Akt phosphorylation in GCs from patients with PCOS and the ovarian tissues from PCOS rats; it also blocked the effects of insulin on apoptosis and proliferation in GCs from patients with PCOS and inhibited caspase-3 activity in ovarian tissues of PCOS rats. Knockdown of klotho gene expression increased the pregnancy rate in DHEA-treated female rats and increased the body weight of their newborns through normalizing the ovarian function and decreasing the formation of cystic follicles. In conclusion, the miR-126-5p, miR-29a-5p/klotho/insulin-IGF-1, Wnt, and Akt signal pathway may be involved in the apoptosis of GCs and subsequent development of PCOS.//////////////////
Expression regulated by
LH, mir15b
Comment
Ovarian localization
Granulosa, Luteal cells, serum
Comment
Low KLOTHOM level related to aging is associated with diminished ovarian reserve. Xu X et al. (2020) To explore the relationship between KLOTHO expression and diminished ovarian reserve (DOR). A case-control study. Reproductive medicine center. A total of 157 patients with DOR and 159 control women were recruited from the Centre of Reproductive Medicine, Peking University Third Hospital. None. The granulosa cells were isolated from follicular fluid after oocyte retrieval, and the KLOTHO level of granulosa cell was measured using a modified quantitative polymerase chain reaction technique. The serum KLOTHO level was measured by solid-phase sandwich enzyme-linked immunosorbent assay. In both granulosa cells and serum derived from women with DOR, KLOTHO expressions were significantly lower compared with normal ovarian reserve controls. Moreover, KLOTHO expression diminished with advancing age. Diminished KLOTHO expression was associated with DOR. Further longitudinal studies in a similar population accompanying disease progression and mechanism exploration are needed to substantiate the rules of KLOTHO in reproductive aging.//////////////////
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: mouse
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: miR-15b induces premature ovarian failure in mice via inhibition of α-Klotho expression in ovarian granulosa cells. Liu T et al. (2019) A thorough understanding of epigenetics regulatory mechanisms of premature ovarian failure (POF) is still lacking. Here, we found that cyclophosphamide induced significantly decrease in α-Klotho (Kl) expression in mouse ovarian granulosa cells (mOGCs), suggesting that cyclophosphamide inhibited Kl expression. Cyclophosphamide also significantly accelerated ageing and led to a decline in the pregnancy rate of C. elegans. We subsequently noted that the pathological condition exhibited by Kl-/- mice was similar to that observed in cyclophosphamide-induced POF mice. Furthermore, the mOGCs in both types of mice showed significant signs of oxidative stress damage, including decreased SOD and ATP, increased ROS levels. Detailed analyses revealed that the decreased Kl expression led to the reduced expression of autophagy-related proteins in mOGCs, which resulted in decreased autophagy activity. Finally, we found that cyclophosphamide attenuated the autophagy function of mOGCs via upregulating microRNA-15b expression, which silenced the endogenous Kl mRNA expression and stimulated the activity of the downstream TGFβ1/Smad pathway. Therefore, we demonstrated that Kl was one of the key inhibitory factors in the development of POF. It elucidated the underlying epigenetic regulatory mechanism, whereby cyclophosphamide-dependent microRNA-15b inhibited Kl expression, leading to the reduced ability of mOGCs to induce autophagy and ROS scavenging, ultimately causing POF.//////////////////
Species: mouse
Mutation name: klotho knockout mouse
type: null mutation fertility: infertile - ovarian defect Comment: 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 (Kuro-o et al., 1997).