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 3

Genetic aberrations identified in patients with impaired or loss of CatSper function.

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Genetic aberrations identified in patients with impaired or loss of CatS...
(A) Schematic depiction of chromosome 15, magnified region q15.3 including genes and the identified deletions (filled color-coded bars) in patients C1–C8, but not patient C9. All positions according to hg19/GRCh37. (B) Schematic depiction of chromosome 1, magnified region q44 and compound-heterozygous variants (see panel D) (c.536G>A and c.2394_2399del) of CATSPERE (NM_001130957.2) identified in patient C9. (C) Family pedigree of patients C1 and C2. Their sister is also homozygous for the deletion at 15q15.3, whereas their mother, father, and third brother are heterozygous carriers. (D) Family pedigree of patient C9, demonstrating that the father and mother are carriers of the missense variant (c.536G>A) and in-frame deletion (c.2394_2399del), respectively. Of note, in ref. 44, we previously showed array-CGH data from patients C1–C5, reporting on the deletion of CATSPER2 in these patients for the first time.