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New Gene Linked to Male Infertility

October 19, 2021
Nikki Novick

A new gene that controls the completion of meiosis in spermatogenesis has been discovered by researchers from Kumamoto University, a Research Center University in Kumamoto, Kumamoto Prefecture in the Kyushu region of Japan. Details of the mechanism that inactivates the expression of genes involved in the meiotic program during spermatogenesis had not been clarified. This has led the researchers to believe that this may lead to an advancement in reproductive medicine, such as identifying causes for infertility from azoospermia or spermatogenic defects. The highest frequency of known genetic factors contributing to male infertility is in azoospermia, although the number of identified genetic anomalies in other semen and aetiological categories continue to grow. 



Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population.There is an exponential recognition of the contribution of genetic abnormalities to the causation of male infertility. Genetic abnormalities account for about 15-30% cases of male infertility which may lead to irreversible partial or complete spermatogenic arrest. About ten percent of genes in the genome are related to spermatogenesis. The formation of spermatozoa occurs in a sequential manner with mitotic, meiotic, and postmeiotic differentiation phases each of which is controlled by an intricate genetic program. Despite the known importance of genetic factors in the event of the man producing no sperm, only about 25% of these cases can be explained currently. 


The increased use of assisted reproduction technology (ART) over the recent years has led to a much greater understanding of the genetic basis of male infertility and the cause of it. A greater understanding of how male infertility can be caused has brought a lot of success in determining the prognosis and management of couples struggling with male infertility. Genetic screening is relevant for its diagnostic value, appropriate genetic counselling and clinical decision-making. In the era of assisted reproduction technology, it is essential to understand the genetic basis of infertility in order to provide maximum adapted therapeutics and counseling to the couple struggling to conceive. 


Genetic disorders cause infertility in men primarily by compromising the production of mature sperm, called spermatogenesis, and its transportation to the egg for fertilization. Image courtesy of medicalxpress.com.  
Genetic disorders cause infertility in men primarily by compromising the production of mature sperm, called spermatogenesis, and its transportation to the egg for fertilization. Image courtesy of medicalxpress.com.  

 

Meiosis is a crucial process for chromosome inheritance to the next generation. Meiosis is a special type of cell division of germ cells in sexually-producing organisms used to produce the gametes, such as sperm or egg cells. It involves two rounds of division that result in four cells with one one copy of each chromosome, therefore reducing the number of chromosomes to half the original. After meiosis is complete, DNA continues to be highly condensed and undergoes major morphological changes that are characteristic of spermiogenesis. This process inactivates the expression of many genes that were previously active in carrying out meiosis in spermatogenesis. 


The genetic landscape of male infertility is extremely complex as semen and testis histological phenotypes are very heterogeneous, and at least 2,000 genes are involved in spermatogenesis. Although, the details of the mechanism that completes the meiotic program at the appropriate time remain unknown, and this being an important issue directly related to reproductive medicine, such as male infertility, it has remained an unresolved issue. 


Professor Ishiguro's group at Kumamoto University’s Institute of Molecular Embryology and Genetics (IMEG) previously discovered MEIOSIN, a gene that switches on meiosis, causing hundreds of genes involved in sperm and egg formation to activate simultaneously. Among them, many genes have functions that are still not fully understood. In the group’s work to ascertain these functions, the researchers selected the ZFP541 gene to analyze in more detail.  


When the function of the ZFP541 gene in mice was eliminated using genome editing, male germ cells started meiosis but died in the process, resulting in infertility due to no sperm being produced. A detailed analysis of the tests of those mice revealed that the ZFP541 gene plays a significant role in the regulation of meiosis and that it is an important gene involved in sperm production. 


Moreover, the ZFP541 gene is expressed in the late meiosis prophase and binds to the regulatory regions, known as promoters, of many meiosis-related genes. Through mass spectrometry analysis, researchers found that ZFP541 binds to an unknown protein called KCTD19 and an enzyme called HDAC1 that has been shown by previous studies to remove acetyl groups from histones. These results show that ZFP541 and HDAC1 together eliminate the histone acetyl group, inactivate the expression of meiosis-related genes, and complete meiosis. 



Meiosis is initiated by MEIOSIN although the details of the mechanism for completing the meiotic phase  by inactivating meiosis-related genes at the right time were unknown. Image courtesy of ewww.kumamoto-u.ac.jp. 
Meiosis is initiated by MEIOSIN although the details of the mechanism for completing the meiotic phase  by inactivating meiosis-related genes at the right time were unknown. Image courtesy of ewww.kumamoto-u.ac.jp


"This research is a follow-up to our discovery of MEIOSIN published in February of 2020 and reveals part of the function of a gene under the control of MEIOSIN whose function is still unknown," said Dr. Yuki Takada, who led the study. "Although these results were verified in mice, ZFP541 is also known to exist in humans. There are many cases of infertility in humans where the cause is unknown, but we expect that this result will contribute to the elucidation of the pathogenesis of infertility, especially those related to sperm dysplasia."

The scientists also believe that their research can be applied to the development of infertility treatment technology. By elucidating the functions of other genes in the process of egg and sperm formation, they hope to make a significant contribution to reproductive medicine.

Due to the wide range of genes involved in the production and transportation of healthy sperm, diagnosing infertility in men due to genetic abnormalities is a complex undertaking. Thanks to researchers like professor Ishiguro’s group, constantly identifying additional genetic anomalies contributing to male infertility, allowing for a significant contribution in determining the prognosis and management of couples struggling with male infertility. 


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