ESPEYB21 14. The Year in Science and Medicine Basic Biology and Molecular Mechanisms (5 abstracts)
14.2. Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation
Young S , Schiffer C , Wagner A , Patz J , Potapenko A , Herrmann L , Nordhoff V , Pock T , Krallmann C , Stallmeyer B , Röpke A , Kierzek M , Biagioni C , Wang T , Haalck L , Deuster D , Hansen JN , Wachten D , Risse B , Behre HM , Schlatt S , Kliesch S , Tüttelmann F , Brenker C & Strünker T.
J Clin Invest. 2024 Jan 2;134(1):e173564. doi: 10.1172/JCI173564
Short summary: This study examined ex vivo the function of the sperm-specific CatSper-channel in almost 2300 men undergoing investigation for infertility. In 9 infertile men with normal semen analysis but pathologic sperm motility, biallelic variants in genes forming the CatSper-channel were found, either in CATSPER2 or CATSPERE. These men and their partners failed to conceive naturally and medically assisted reproduction (MAR) was successful only via intracytoplasmic sperm injection (ICSI). The study team developed a ‘CatSper-Activity-Test’, which was used in combination with [Ca2+]i fluorimetric and electrophysiological recordings to systematically assess the function of CatSper in human sperm, showing the patho-aetiology of CatSper deficiency.
In mammals, sperm motility is controlled by changes in the intracellular Ca2+ concentration through CatSper. Previous studies in mice showed that targeted ablation of genes encoding CatSper subunits did not affect sperm number, morphology, or basal motility, but resulted in failure to switch to the so-called hyperactive motility mode. Although human genetic variants in genes of the CatSper channel were described before, their disease-causing mechanism was unclear.
This study shows that CatSper-deficient human sperm are unable to switch into the hyperactivity mode necessary to penetrate the egg coat for fertilization. This explains the infertility of CatSper-deficient men and the failure of MAR support via ovulation induction, intrauterine insemination, or in vitro fertilization, which are currently methods of first choice for couples with unexplained infertility.
After current investigations for infertility in men, one third remains unexplained. It is estimated that variants in genes forming the CatSper channel complex are the most common underlying cause for this group. Thus, the study team suggests maybe rightfully that their “CatSper-Activity-Test” could be performed as part of routine semen analysis to identify patients with a sperm channelopathy and inform personalised selection of the MAR technique. This may reduce time to reproductive success, psychological burden and expenses for many affected couples.
As a final note: So far, genetic analysis of families with clustering of male-factor infertility (due to consanguinity) identified individuals with disease-causing variants in the CATSPER1-3 genes, the CATSPERE gene and with a homozygous deletion of CATSPER2 and the contiguous gene STRC. The latter was termed deafness-infertility syndrome (OMIM 611102) because deletion of STRC causes mild-to-moderate hearing loss, which might serve as a diagnostic hint towards defective CatSper when found in infertile men.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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