A novel copy number variation in <i>CATSPER2</i> causes idiopathic male infertility with normal semen parameters

Luo, Tao; Chen, Houyang; Zou, Qianxing; Wang, Tao; Chen, Yimin; Wang, Huafeng; Wang, Fang; Jin, Zhong-Lin; Chen, Ying; Weng, Shiqi; Zeng, Xuhui

doi:10.1093/humrep/dey377

Cited by 65 publications

(78 citation statements)

References 28 publications

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“…Whether exposure of the human sperm cells, either within the male or female reproductive tract, to environmental chemicals acting on CatSper can interfere with the fertilization process remains to be shown. However, the fact that impaired progesterone-signaling is associated with reduced male fertility (14)(15)(16)(17)(18)(19)(20) and that men who lack functional CatSper are completely infertile (18,(21)(22)(23)(24)(25)(26)(27)(28)(29) hints that environmental chemicals interfering with this signaling pathway could make it more difficult for the human sperm cells to successfully locate and fertilize the oocyte. As our experiments have been performed on sperm cells in vitro future studies would be needed to validate our results and to examine the effects of exposure to bisphenols on fertility in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of CatSper by progesterone controls important sperm functions (13). A suboptimal progesterone-induced Ca 2+ influx is associated with reduced male fertility (14)(15)(16)(17)(18)(19)(20) and men who lack functional CatSper are sterile (18,(21)(22)(23)(24)(25)(26)(27)(28)(29), illustrating the importance of CatSper and Ca 2+ signaling for normal male fertility. Studies have shown that human CatSper can be promiscuously activated by various signaling molecules (30), steroids (31,32), small molecules (33), and environmental chemicals (34)(35)(36)(37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

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Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

2020

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Aim: Evidence suggests that bisphenol A diglycidyl ether (BADGE), bisphenol A (BPA), and BPA analogs can interfere with human male fertility. However, the effect directly on human sperm function is not known. The CatSper Ca 2+ channel in human sperm controls important sperm functions and is necessary for normal male fertility. Environmental chemicals have been shown to activate CatSper and thereby affect Ca 2+ signaling in human sperm. BPA has previously been investigated for effects on Ca 2+ signaling human sperm, whereas the effects of other BPA analogs are currently unknown. The aim of this study is thus to characterize the effect of BADGE, BPA, and the eight analogs BPG, BPAF, BPC, BPB, BPBP, BPE, BPF, BPS on Ca 2+ signaling, and CatSper in human sperm. Methods: Direct effects of the bisphenols on Ca 2+ signaling in human sperm cells were evaluated using a Ca 2+ fluorimetric assay measuring changes in intracellular Ca 2+. Effects via CatSper were assessed using the specific CatSper inhibitor RU1968. Effects on human sperm function was assessed using an image cytometry-based acrosome reaction assay and the modified Kremer's sperm-mucus penetration assay. Results: At 10 µM the bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP induced Ca 2+ signals in human sperm cells, whereas BPE, BPF, BPS, and BPA had no effect. The efficacy of the chemicals at 10 µM is BPG > BPAF > BPC > BADGE > BPB > BPBP. Dose-response relations of BPG, BPAF, BPC, BADGE, BPB, and BPBP yielded EC50-values in the nM-µM range. The induced Ca 2+ signals were almost completely abolished using the CatSper inhibitor RU1968, indicating an effect of the bisphenols on CatSper. All bisphenols, except BPBP, were found to dose-dependently inhibit progesterone-induced Ca 2+ signals, with BPG and BPAF displaying inhibition even in low µM doses. BPG and BPAF were shown to affect human sperm function in a progesterone-like manner. Rehfeld et al. Bisphenols Activate Human CatSper Conclusion: Our results show that the bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP can affect Ca 2+ signaling in human sperm cells through activation of CatSper. This could potentially disrupt human sperm function by interfering with normal CatSpersignaling and thus be a contributing factor in human infertility, either alone or in mixtures with other chemicals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

2020

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“…The CatSper channel (cation channel of sperm) represents the principal pathway for Ca 2+ entry into the flagellum of sperm from many species (1)(2)(3)(4)(5)(6)(7). The activity of CatSper is controlled by both the membrane potential (V m ) and intracellular pH (pH i ) (2)(3)(4)6,8,9), and, in human sperm, also by oviductal steroids and prostaglandins (3,4,(10)(11)(12)(13)(14). Thereby, CatSper translates changes of the chemical microenvironment into changes of [Ca 2+ ] i and swimming behavior, which enables sperm to reach the site of fertilization, to overcome the egg´s protective vestments, and, ultimately, to fertilize the egg (1,(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…Thereby, CatSper translates changes of the chemical microenvironment into changes of [Ca 2+ ] i and swimming behavior, which enables sperm to reach the site of fertilization, to overcome the egg´s protective vestments, and, ultimately, to fertilize the egg (1,(14)(15)(16)(17)(18)(19)(20). CatSper is, hence, absolutely required for fertilization in mice and humans (1,11,13,14,(21)(22)(23)(24). Not only the control of [Ca 2+ ] i by CatSper, but also the flagellar cAMP dynamics is key for the function of sperm (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA

Wang

Young

Krenz

et al. 2020

Journal of Biological Chemistry

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The sperm-specific CatSper channel controls the influx of Ca2+ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing activation of protein kinase A (PKA) is, however, a matter of controversy. To shed light on this question, we used kinetic ion-sensitive fluorimetry, patch-clamp recordings, and optochemistry to study transmembrane Ca2+ flux and membrane currents in human sperm from healthy donors and from patients that lack functional CatSper channels. We find that human CatSper is neither activated by intracellular cAMP directly nor indirectly by the cAMP/PKA-signaling pathway. Instead, we show that non-physiological concentrations of cAMP and membrane-permeable cAMP analogs used to mimic the action of intracellular cAMP activate human CatSper from the outside via a hitherto unknown extracellular binding site. Finally, we demonstrate that the effects of common PKA inhibitors on human CatSper rest predominantly, if not exclusively, on off-target drug actions on CatSper itself rather than on inhibition of PKA. We conclude that the concept of an intracellular cAMP/PKA-activation of CatSper is primarily based on unspecific effects of chemical probes used to interfere with cAMP signaling. Altogether, our findings solve several controversial issues and reveal a novel ligand-binding site controlling the activity of CatSper, which has important bearings on future studies of cAMP and Ca2+ signaling in sperm.

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“…Genetic disruption of CATSPER ZETA or EFCAB9 expression causes subfertility and reduced CatSper expression within disorganized CatSper signalling domains (Chung et al., 2017; Hwang et al., 2019). Importantly, genomic errors at CatSper subunit loci are reported in infertile men (Avidan et al., 2003; Avenarius et al., 2009; Bhilawadikar et al., 2013; Jaiswal et al., 2014; Brown et al., 2018; Luo et al., 2019). Therefore, there is significant genetic evidence to argue that CatSper is essential for male fertility in mouse and humans.…”

Section: Catspermentioning

confidence: 99%

Human sperm ion channel (dys)function: implications for fertilization

Brown

Publicover

Barratt

et al. 2019

Human Reproduction Update

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BACKGROUNDIntensive research on sperm ion channels has identified members of several ion channel families in both mouse and human sperm. Gene knock-out studies have unequivocally demonstrated the importance of the calcium and potassium conductances in sperm for fertility. In both species, the calcium current is carried by the highly complex cation channel of sperm (CatSper). In mouse sperm, the potassium current has been conclusively shown to be carried by a channel consisting of the pore forming subunit SLO3 and auxiliary subunit leucine-rich repeat-containing 52 (LRRC52). However, in human sperm it is controversial whether the pore forming subunit of the channel is composed of SLO3 and/or SLO1. Deciphering the role of the proton-specific Hv1 channel is more challenging as it is only expressed in human sperm. However, definitive evidence for a role in, and importance for, human fertility can only be determined through studies using clinical samples.OBJECTIVE AND RATIONALEThis review aims to provide insight into the role of sperm ion channels in human fertilization as evidenced from recent studies of sperm from infertile men. We also summarize the key discoveries from mouse ion channel knock-out models and contrast the properties of mouse and human CatSper and potassium currents. We detail the evidence for, and consequences of, defective ion channels in human sperm and discuss hypotheses to explain how defects arise and why affected sperm have impaired fertilization potential.SEARCH METHODSRelevant studies were identified using PubMed and were limited to ion channels that have been characterized in mouse and human sperm. Additional notable examples from other species are included as appropriate.OUTCOMESThere are now well-documented fundamental differences between the properties of CatSper and potassium channel currents in mouse and human sperm. However, in both species, sperm lacking either channel cannot fertilize in vivo and CatSper-null sperm also fail to fertilize at IVF. Sperm-lacking potassium currents are capable of fertilizing at IVF, albeit at a much lower rate. However, additional complex and heterogeneous ion channel dysfunction has been reported in sperm from infertile men, the causes of which are unknown. Similarly, the nature of the functional impairment of affected patient sperm remains elusive. There are no reports of studies of Hv1 in human sperm from infertile men.WIDER IMPLICATIONSRecent studies using sperm from infertile men have given new insight and critical evidence supporting the supposition that calcium and potassium conductances are essential for human fertility. However, it should be highlighted that many fundamental questions remain regarding the nature of molecular and functional defects in sperm with dysfunctional ion channels. The development and application of advanced technologies remains a necessity to progress basic and clinical research in this area, with the aim of providing effective screening methodologies to identify and develop treatments for affected men in order t...

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A novel copy number variation in CATSPER2 causes idiopathic male infertility with normal semen parameters

Cited by 65 publications

References 28 publications

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

Bisphenol A Diglycidyl Ether (BADGE) and Bisphenol Analogs, but Not Bisphenol A (BPA), Activate the CatSper Ca2+ Channel in Human Sperm

The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA

Human sperm ion channel (dys)function: implications for fertilization

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