The molecular role of M1AP in meiotic arrest

• Applicant: Dr. Corinna Friedrich
• Subject Area: Reproductive Medicine, Urology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329621271

In western societies, ~7% of all males are infertile, but the underlying causes often remain elusive. Azoospermia is the most severe form and is defined by the complete lack of sperm in the ejaculate. Non-obstructive azoospermia (NOA) is in part caused by meiotic arrest at the spermatocyte stage and no mature spermatids can be found within the testis. We recently identified Meiosis 1 arresting protein (M1AP) as novel autosomal-recessive candidate gene for meiotic arrest and NOA. In our Male of Reproductive Genetics (MERGE) cohort comprising more than 900 exomes of infertile men and 64 with meiotic arrest, we identified three men with a recurrent homozygous loss-of-function (LoF) variant in M1AP. This result 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 from our finding, M1AP was identified as causal gene for male infertility in a consanguineous family from Turkey. A previously published M1AP knockout mouse was described as infertile and showed a comparable histological phenotype as the patients but is no longer available for further characterisation. In men and mice, M1AP is predominantly expressed in the testis. Thus, it is assumed 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 M1AP. 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 biochemistry and microscopy 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 more detail.In perspective, we will shed more light onto specific meiotic processes and the origin of meiotic arrest leading to male infertility. We will further decrease the percentage of unsolved male infertility cases by proposing novel candidate genes among identified M1AP interaction partners.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 326: Male Germ Cells: from Genes to Function