O-017 A novel diagnostic test identifies patients suffering from loss of CatSper function
Authors: Young S , Schiffer C , Wagner A , Patz J , Potapenko A , Herrmann L , Pock T , Stallmeyer B , Röpke A , Nordhoff V , Behre H , Kliesch S , Tüttelmann F , Brenker C , Strünker T 
Published: June 2023

Abstract

Study question
Is a loss of CatSper function in sperm a common cause of unexplained male infertility?

Summary answer
Loss of CatSper function leads to similar infertility phenotypes in mice and men and represents one of the most common causes of unexplained male infertility.

What is known already
Male infertility is often due to low sperm counts, impaired motility, and/or abnormal morphology. However, for a large fraction of infertile men, semen parameters are normal, suggesting that the infertility is rather due to an unexplained dysfunction of the sperm. There has been a growing body of evidence that human sperm dysfunction might involve the sperm-specific Ca2+ channel CatSper (cation channel of sperm) that translates changes in the chemical microenvironment of the female reproductive tract into changes in swimming behavior.

Study design, size, duration
In an observational study over the course of three years, a prototype of the “CatSper-Activity-Test” (CAT) was used to assess the function of CatSper in sperm from the left-over semen samples of 2286 unselected patients undergoing a semen analysis.

Participants/materials, setting, methods
The CatSper-Activity-Test (CAT) was developed at the Centre of Reproductive Medicine and Andrology, University Hospital Münster and subsequently performed by medical technical assistants in the diagnostic facility of this institution. Requiring only 40 µl of ejaculate, a standard light microscope, and a hands-on-time of a few minutes, the CAT enables a read-out of the activity of CatSper through a motility response: in the CAT buffer, CatSper-intact, but not CatSper-deficient sperm become immotile.

Main results and the role of chance
Using this CatSper-Activity-Test, we identified seven patients suffering from a loss of CatSper function in a cohort of men seeking medical advice for suspected male infertility. Standard semen analysis revealed that the CatSper-deficient patients are (with one exception) normozoospermic and were diagnosed with unexplained infertility. Notably, their sperm not only failed to fertilize the egg naturally but also upon intrauterine insemination (IUI) and in vitro fertilization (IVF), whereas intra-cytoplasmic sperm injection (ICSI) was successful. Two additional CatSper-deficient patients were identified among patients visiting our clinics for other reasons. We show that the loss of CatSper function is predominantly caused by a homozygous deletion of the CATSPER2 gene; one patient featured compound heterozygous variants of the CATSPERE gene. According to the study results, CatSper dysfunction underlies 1.7% of cases of unexplained male infertility, for which a female factor can be excluded.

Limitations, reasons for caution
Results from this observational study were obtained from a single institute. A multi-center study involving various countries would enable a more precise determination of the prevalence of CatSper-related male infertility.

Wider implications of the findings
The CatSper-Activity-Test reliably identifies CatSper-deficient patients with a hands-on-time of a few minutes and requires neither special equipment nor specific training. We envisage the CatSper-Activity-Test as a novel tool for the early diagnosis of male infertility, thus, contributing to evidence-based treatment decisions and sparing patients unnecessary medical and financial risks.

Trial registration number
not applicable