Genomics of severe spermatogenic failure

• Applicant: Professor Dr. Frank Tüttelmann
• Subject Area: Reproductive Medicine, Urology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329621271

Male infertility is in most cases characterised by spermatogenic failure, i.e. reduced sperm production identified by semen analysis. Non-obstructive azoospermia (NOA), the complete lack of spermatozoa in the ejaculate, is the clinically most severe form and a testicular biopsy aiming for sperm extraction is the only chance for parenthood. Genetic causes are suspected in the majority of azoospermic patients, but to date more than 50% of affected men remain without causal diagnoses, i.e. unexplained (‘idiopathic’).Within this CRU, we established one of the largest exome datasets of infertile men including >500 NOA patients and, thereof, >200 with histologically proven Sertoli-cell only phenotype (SCO, no germ cells in the testis) and >60 with an arrest of spermatogenesis at meiosis. These data allowed for the identification of several novel genes, in which mutations cause NOA. Examples are TEX11, STAG3, SYCP2, and M1AP. For some of these genes, the molecular role during spermatogenesis has been shown e.g. in model systems. For others, the function of the encoded protein remains elusive, which is the starting point for subsequent analyses. Likewise, variants in these genes may be benign or pathogenic, but without proper assays the assessment is solely based on in silico predictions. Thus, we will establish in vitro test systems to examine patient-specific variants in e.g. the genes NR5A1, DMRT1, and AR. To identify novel candidate genes, we will significantly increase the number of exome sequenced patients with specific phenotypes. A complementary fertility screen in Drosophila melanogaster will reveal conserved genes required for spermatogenesis. Taken together, we will assay variants in known genes associated with NOA as well as identify novel genes and analyse their function(s).Consequently, we will significantly increase the genetic diagnostic yield in infertile men with severe spermatogenic failure such as azoospermia. This will pave the way for well-informed treatment decisions, estimating risks, and better counselling.

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