In western societies, ~7% of all men are infertile, but the underlying causes often remain elusive. Azoospermia is the most severe form and is defined by a complete lack of spermatids in the ejaculate. One important clinical challenge is to distinct between azoospermia due to spermatogenic failure (non-obstructive azoospermia, NOA) and obstructive azoospermia (OA). However, this is highly critical for the optimal counselling and treatment of patients. Genetic causes for NOA are often suspected, but only few disease-associated genes have been identified yet.
Male meiosis is a complex step during spermatogenesis. Aberrant gene expression can causes an arrest of this process (meiotic arrest, MeiA) leading to the lack of fertilisation-competent germ cells. Identifying novel genes and deciphering the underlying mechanisms of impaired meiosis is essential for a deeper understanding of spermatogenesis and NOA and, thus, displays the focus of our research.
Within one of our projects, we recently identified meiosis 1 arresting protein (M1AP) as a novel autosomal-recessive candidate gene causing meiotic arrest, NOA and leading to male infertility (Wyrwoll et al., 2020).
In our MERGE cohort (Male Reproductive Genomics, ~200 new cases per year, internal and external recruitment) comprising the exomes of infertile men, we identified three men with a homozygous loss-of-function (LoF) variant in M1AP resulting in a severely truncated and therefore very likely non-functional protein. Our finding was validated by the identification of three additional men with NOA in cohorts from our collaboration partners of the International Male Infertility Genomics Consortium (IMIGC). Independently of our finding, M1AP was identified as a causal gene for male infertility in a consanguineous family from Turkey. A previously published M1AP knockout mouse was described as infertile and showed a histological phenotype comparable to the patients. In men and mice, M1AP is predominantly expressed in the testis. We therefore provide multiple lines of evidence that M1AP plays a crucial role during spermatogenesis and meiosis.
Very little is known about the precise expression pattern, the subcellular localisation or the cellular function of the M1AP protein. Therefore, we aim to investigate M1AP on several levels: by expressing M1AP in cellular model systems, analysing human testicular samples, and generating a new knockout mouse using molecular biological, protein biochemical, and microscopical techniques, we will examine M1AP under impaired and wildtype conditions. Finally, we aim to identify interaction partners of M1AP using biomolecular mass spectrometry. This will identify additional candidate genes for male infertility and further elucidate the cellular network of M1AP.
In perspective, our project will shed more light onto specific meiotic processes and the origin of meiotic arrest leading to male infertility and further decrease the percentage of unsolved male infertility cases.