Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation
Samuel Young, … , Christoph Brenker, Timo Strünker
Samuel Young, … , Christoph Brenker, Timo Strünker
Published January 2, 2024
Citation Information: J Clin Invest. 2024;134(1):e173564. https://doi.org/10.1172/JCI173564.
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Research Article Cell biology Reproductive biology

Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation

Abstract

The infertility of many couples rests on an enigmatic dysfunction of the man’s sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of men with normal semen parameters but defective CatSper function. These men or couples failed to conceive naturally and upon medically assisted reproduction via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, our study provides the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and the need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.

Authors

Samuel Young, Christian Schiffer, Alice Wagner, Jannika Patz, Anton Potapenko, Leonie Herrmann, Verena Nordhoff, Tim Pock, Claudia Krallmann, Birgit Stallmeyer, Albrecht Röpke, Michelina Kierzek, Cristina Biagioni, Tao Wang, Lars Haalck, Dirk Deuster, Jan N. Hansen, Dagmar Wachten, Benjamin Risse, Hermann M. Behre, Stefan Schlatt, Sabine Kliesch, Frank Tüttelmann, Christoph Brenker, Timo Strünker

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Figure 2

Ca2+ signals and membrane currents in sperm from patients with impaired or loss of CatSper function.

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Ca2+ signals and membrane currents in sperm from patients with impaired ...
(A) Representative Ca2+ signals in sperm from donors and patients C1–C9 (color coded) evoked by progesterone (3 μM), PGE1 (3 μM), or NH4Cl (30 mM) relative to the maximal signal amplitude evoked by ionomycin (3 μM) (set to 1). (B) Mean (± SD) maximal signal amplitude evoked by progesterone (gray; donors n = 11, C1-C8 n = 1, C9 n = 3), PGE1 (orange; donors n = 10, C1,2,4-8 n = 1, C9 n = 3), or NH4Cl (blue; donors n = 6, C1,2,8 n = 1, C9 n = 3) relative to that evoked by ionomycin (set to 1). (C) Representative whole-cell currents recorded from a sperm cell of a donor and patient C6 in extracellular solution containing Mg2+ and Ca2+ (HS) and in Na+-based divalent-free solution (NaDVF), evoked by stepping the membrane voltage to –100mV, +100 mV, and +150 mV from a holding potential of –80 mV. (D) Steady-state current amplitudes (NaDVF) at +100 mV and –100 mV in sperm from donors (black, n = 10) and patients C1–C8 (color coded, n = 1). (E) Representative whole-cell currents recorded from patients C6 (black) and C9 (red) in NaDVF, evoked by stepping the membrane voltage from to –100mV, +100 mV, and +150 mV from a holding potential of –80 mV. (F) Steady-state current amplitudes at +150 mV and –100 mV in NaDVF in sperm from patients C1–C7 and C1–C8, respectively, (color coded; n = 1) as shown in C (consider the scales of Y-axes) compared to patient C9 (light green, n = 3). Data on Ca2+ responses and membrane currents in sperm from patients C1–C5 comprise data from ref. 44, reporting on these patients for the first time, combined with data from additional experiments.