Unexplained infertility is frequently caused by defective CatSper function preventing sperm from penetrating the egg coat

• DOI: 10.1101/2023.03.23.23286813
• Publication Date: 2023-03-27T22:05:13Z
• 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

The infertility of many couples seems to rest on an enigmatic dysfunction of the men’s sperm, rendering early diagnosis and evidence-based treatment by medically assisted reproduction impossible. Using a novel laboratory test, we assessed the function of the flagellar Ca2+channel CatSper in sperm of almost 2,300 men undergoing a fertility workup. Thereby, we identified a group of men with mutations inCATSPERgenes affecting the function of the channel. Although standard semen and computer-assisted sperm analysis were unremarkable, the couples required intracytoplasmic sperm injection (ICSI) to conceive a child. We show that their seemingly unexplained infertility and need for ICSI is, in fact, due to the failure of CatSper-deficient human sperm to hyperactivate and penetrate the egg coat. In summary, our study reveals that defective CatSper function represents the most common cause of unexplained male-factor infertility known thus far and that CatSper-related infertility can readily be diagnosed, enabling evidence-based treatment.