Mutation analysis of three genes in patients with maturation arrest of spermatogenesis and couples with recurrent miscarriages

The primary aim of this study was to gain more insight into maturation arrest of spermatogenesis (MA) and its relationship with mutations in genes essential for meiosis. The study also investigated the possibility that mutations in human meiosis genes cause a milder phenotype and that, in such cases, meiosis could potentially be completed with the production of mature germ cells having an abnormal chromosomal constitution causing miscarriage. Among 40 patients with MA, five changes were observed that also predicted alterations at the amino acid level. However, since these changes were also present in men with normozoospermia in equal frequencies, it was assumed that these changes are single nucleotide polymorphisms. Among 46 patients with recurrent miscarriages, two additional changes were detected predicting an alteration at the amino acid level. One change was detected in controls. However, the second heterozygous change, detected in a conserved functional domain of the SYCP3 gene, was absent in >200 controls. These preliminary results stress the need to further investigate the relationship between abnormalities in meiosis genes and the formation of gametes with abnormal chromosomal constitution. More research is also necessary to determine the impact and frequency of such changes before implementing mutation screening in genetic counselling.Our primary aim was to gain more insight into maturation arrest of spermatogenesis (MA). Patients with MA are infertile due to the absence of sperm cells in their ejaculates. A biopsy of the testis of these patients showed that the germ cells stopped developing at a level called meiosis. During meiosis the chromosomes are divided into two daughter cells. We looked for the presence of alterations in genes essential for meiosis. We also investigated the possibility that modifications in human meiosis genes are causing a milder effect and that in such cases meiosis could potentially be completed with the production of mature germ cells having an abnormal chromosomal constitution. These abnormal germ cells might cause recurrent miscarriages after fertilization. Several changes in three investigated genes were detected. Most of these alterations were also observed in a control group consisting of men with normal semen parameters or men who fathered at least one child. Therefore, these modifications are most likely not the cause of the problems in the patients. However, one change present in an evolutionary important functional domain of the SYCP3 gene was detected in the male partner of a couple suffering from recurrent miscarriages and was absent in >200 controls. Despite our small patient groups, these preliminary results confirm our assumption that abnormalities in meiosis genes might be involved in the formation of gametes with abnormal chromosomal constitution. Yet, further research is necessary to determine the impact and frequency of such changes before implementing mutation screening in genetic counselling.