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cystic fibrosis transmembrane conductance regulator OKDB#: 2954
 Symbols: CFTR Species: human
 Synonyms: CF, MRP7, ABC35, ABCC7, CFTR/MRP, TNR-CFTR, dJ760C5.1  Locus: 7q31.2 in Homo sapiens


For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment NCBI Summary: This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
General function Channel/transport protein
Comment Impaired CFTR-Dependent Amplification of FSH-Stimulated Estrogen Production in Cystic Fibrosis and PCOS. Chen H et al. Context:Estrogens play important roles in a wide range of physiological and pathological processes, and their biosynthesis is profoundly influenced by FSH that regulates the rate-limiting enzyme aromatase-converting estrogens from androgens. Abnormal estrogen levels are often seen in diseases such as ovarian disorders in polycystic ovarian syndrome (PCOS), an endocrine disorder affecting 5-10% of women of reproductive age, and cystic fibrosis (CF), a common genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR).Objectives:We undertook the present study to investigate the mechanism underlying these ovarian disorders, which is not well understood.Results:FSH-stimulated cAMP-responsive element binding protein phosphorylation, aromatase expression, and estradiol production are found to be enhanced by HCO(3)(-) and a HCO(3)(-) sensor, the soluble adenylyl cyclase, which could be significantly reduced by CFTR inhibition or in ovaries or granulosa cells of cftr knockout/?F508 mutant mice. CFTR expression is found positively correlated with aromatase expression in human granulosa cells, supporting its role in regulating estrogen production in humans. Reduced CFTR and aromatase expression is also found in PCOS rodent models and human patients.Conclusions:CFTR regulates ovarian estrogen biosynthesis by amplifying the FSH-stimulated signal via the nuclear soluble adenylyl cyclase. The present findings suggest that defective CFTR-dependent regulation of estrogen production may underlie the ovarian disorders seen in CF and PCOS.
Cellular localization Plasma membrane
Comment CFTR and FOXO1 gene expression are reduced and high mobility group box 1 (HMGB1) is increased in the ovaries and serum of women with polycystic ovarian syndrome. Cirillo F et al. (2019) We previously described increased HMGB1 and reduced FOXO1 dependent on CFTR loss of function in cystic fibrosis (CF) and we showed in vitro that HMGB1 was lowered by insulin. Reduced CFTR gene expression has been described in granulosa cells (GC) from PCOS-induced rats. We aimed at studying CFTR and FOXO1 gene expression in GC, HMGB1 concentrations in serum and follicular fluids (FF), and insulin and IL-6 in FF in PCOS women. Thirty PCOS and 36 non-PCOS women (CTRL) undergoing in vitro fertilization were enrolled. CFTR and FOXO1 gene expression were downregulated in PCOS (p ≤ .05). HMGB1 was higher in PCOS both in FF (p ≤ .05) and in serum (p < .005) whereas insulin was lower, and IL-6 was unchanged with respect to controls. 17-β estradiol was higher in PCOS than in CTRL (p ≤ .005). HMGB1 correlated negatively with insulin in FF (p ≤ .005). The increase in HMGB1 both in FF and in serum, likely reflects both low grade inflammation and insulin sensitivity. IL-6 was unchanged possibly reflecting functions other than inflammation.//////////////////
Ovarian function Antrum/Follicular fluid formation, Ovulation, Steroid metabolism, Luteinization
Comment Amplification of FSH signaling by CFTR and nuclear soluble adenylyl cyclase in the ovary. Chen H et al. (2017) cAMP/PKA pathway is one of the most important signaling pathways widely distributed in most eukaryotic cells. The activation of the canonical cAMP/PKA pathway depends on transmembrane adenylyl cyclase (tmAC). Recently, soluble adenylyl cyclase (sAC), which is activated by HCO3(-) or Ca(2+) , emerges to provide an alternative way to activate cAMP/PKA pathway with the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl(-) / HCO3(-) -conducting anion channel, as a key player. This review summarizes new progress in the investigation of the CFTR/HCO3(-) -dependent sAC signaling and its essential role in various reproductive processes, particularly in ovarian functions. We present the evidence for a CFTR/HCO3(-) -dependent nuclear sAC signaling cascade that amplifies the FSH-stimulated cAMP/PKA pathway, traditionally thought to involve tmAC, in granulosa for the regulation of estrogen production and granulosa cell proliferation. The implication of the CFTR/HCO3(-) /sAC pathway in amplifying other receptor-activated cAMP/PKA signaling in a wide variety of cell types and pathophysiological processes, including aging, is also discussed. This article is protected by copyright. All rights reserved.////////////////// Estrogen-induced abnormally high cystic fibrosis transmembrane conductance regulator expression results in ovarian hyperstimulation syndrome Ajonuma LC, et al . Ovarian hyperstimulation syndrome (OHSS) remains one of the most life-threatening and potentially fatal complications of assisted reproduction treatments, arising from excessive stimulation of the ovaries by exogenous gonadotropins administrated during in vitro fertilization procedures, which is characterized by massive fluid shift and accumulation in the peritoneal cavity and other organs, including the lungs and the reproductive tract. The pathogenesis of OHSS remains obscure, and no definitive treatments are currently available. Using RT-PCR, Western blot, and electrophysiological techniques we show that cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel expressed in many epithelia, is involved in the pathogenesis of OHSS. Upon ovarian hyperstimulation, rats develop OHSS symptoms, with up-regulated CFTR expression and enhanced CFTR channel activity, which can also be mimicked by administration of estrogen, but not progesterone, alone in ovariectomized rats. Administration of progesterone that suppresses CFTR expression or antiserum against CFTR to OHSS animals results in alleviation of the symptoms. Furthermore, ovarian hyperstimulation does not induce detectable OHSS symptoms in CFTR mutant mice. These findings confirm a critical role of CFTR in the pathogenesis of OHSS and may provide grounds for better assisted reproduction treatment strategy to reduce the risk of OHSS and improve in vitro fertilization outcome.
Expression regulated by FSH, LH
Comment
Ovarian localization Granulosa, Theca
Comment Expression of cystic fibrosis transmembrane conductance regulator in rat ovary. Jin L et al. The protein expression of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl(-) channel, in ovarian stimulated premature female rat ovary during a cycle of follicle development and corpus luteum formation was investigated. Animals were injected with 10 U pregnant Mare's serum gonadotropin (PMSG) and subsequently 10 U hCG 48 h later. Time-dependent immunohistochemistry and Western blotting experiments were performed before and 24, 48, 72 h after hCG treatment. The immunohistochemistry revealed that administration of PMSG stimulated the CFTR expression in thecal cell layer and granulosa cell layer of mature follicles 48 h post injection, coincident with the PMSG-induced peak in follicular estradiol. However, the expression of CFTR in the granulose lutein cell layer and thecal lutein cell layer was time-dependently reduced following hCG injection, in accordance with the gradually increased progestogen level during luteum corpus formation. Western blotting analysis demonstrated that rat ovarian tissue expressed the special CFTR band at 170 kD. It is concluded that cAMP-dependent Cl(-) channels are involved in regulation of follicle development and luteum formation.
Follicle stages Preovulatory
Comment Defective CFTR-regulated granulosa cell proliferation in PCOS. Chen H et al. (2015) Polycystic ovarian syndrome (PCOS) is one of the most frequent causes of female infertility, featured by abnormal hormone profile, chronic oligo/anovulation and presence of multiple cystic follicles in the ovary. However, the mechanism underlying the abnormal folliculogenesis remains obscure. We have previously demonstrated that CFTR, a cAMP-dependent Cl- and HCO3- -conducting anion channel, is expressed in the granulosa cells and its expression is downregulated in PCOS rat models and human patients. In the present study, we aimed to investigate the possible involvement of downregulation of CFTR in the impaired follicle development in PCOS using two rat PCOS models and primary culture of granulosa cells. Our results showed that the downregulation of CFTR in the cystic follicles was accompanied by reduced expression of PCNA, in rat PCOS models. In addition, knockdown or inhibition of CFTR in granulosa cell culture resulted in reduced cell viability and downregulation of PCNA. We further demonstrated that CFTR regulated both basal and FSH-stimulated granulosa cell proliferation through the HCO3-/sAC/PKA pathway leading to ERK phosphorylation and its downstream target CyclinD2 (Ccnd2) upregulation. Reduced ERK phosphorylation and CCND2 were found in ovaries of rat PCOS model compared to the control. The present study suggests that CFTR is required for normal follicle development and that its downregulation in PCOS may inhibit granulosa cell proliferation, resulting in abnormal follicle development in PCOS.//////////////////
Phenotypes PCO (polycystic ovarian syndrome)
Mutations 1 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Female cystic fibrosis mutation carriers and assisted reproductive technology: does carrier status affect reproductive outcomes? VanWort TA 2014 et al. OBJECTIVE To evaluate the association between female cystic fibrosis (CF) carrier status and in vitro fertilization (IVF) response and outcomes. The presence of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in male carriers has been associated with infertility, yet possible adverse effects on the ovarian function and reproductive outcomes of female carriers have not been studied to date. DESIGN Retrospective cohort study. SETTING Private academic, clinical reproductive center. PATIENT(S) Females <40years of age who were screened for CFTR mutations and received IVF treatment between July 2002 and March2013. INTERVENTION(S) Patients initiated controlled ovarian hyperstimulation with frequent monitoring, vaginal oocyte retrieval, fertilization, embryo transfer, and a pregnancy test. Various measures of IVF stimulation response and cycle outcome were evaluated for both carriers and noncarriers. MAIN OUTCOME MEASURE(S) Analysis was performed by logistic regression and Poisson regression. RESULT(S) IVF cycles (n = 199) from CFTR mutation carrier patients (n = 112) were analyzed. No significant differences in outcome were noted when carriers of different mutation loci were compared in aggregate with the noncarrier group (n = 6,420 cycles from 3,555 patients). Significant differences were noted for some metrics when the carriers were grouped by mutation loci. CONCLUSION(S) Overall, no significant differences in stimulation response and cycle outcome were noted between female CFTR mutation carriers and noncarriers. Further research is needed to investigate whether the differences noted between specific CFTR mutation loci are clinically relevant and whether CFTR mutations may impact reproductive outcomes outside the context of assisted reproductive technologies. /////////////////////////

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created: Dec. 10, 2005, 5:21 p.m. by: hsueh   email:
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last update: April 10, 2019, 10:16 a.m. by: hsueh    email:



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