Male infertility caused by defective sperm flagella beat generation due to ODA defects

点击翻译按钮获取中文摘要

Sperm flagella are evolutionary conserved organelles that contain a 9+2- microtubule structure also present in multiple motile cilia. The flagellar and ciliary beat generation is produced by outer dynein arms (ODA). These multimeric protein complexes generate by ATP hydrolysis, the driving force of microtubule sliding. Outer dynein arm defects are associated with the motile ciliopathy primary ciliary dyskinesia (PCD, ORPHA 244). This rare inherited disorder is genetically, functionally, and ultrastructurally heterogeneous. Respiratory cilia and mucociliary clearance causing a chronic destructive airway disease are hallmark findings in PCD, but also male infertility due to compromised sperm flagella motility (asthenozoospermia) is part of the disease spectrum. Our studies have shown that the composition of sperm flagella axonemes differ from motile cilia such as respiratory cilia. Not surprisingly, several genes encoding for axonemal components were identified to be specifically related to dysfunction of sperm flagella without affecting mucociliary clearance. Within the first funding period we identified three novel genetic defects resulting in ODA defects affecting male fertility. In addition we characterized the ODA composition of sperm flagella and motile cilia, including those of the efferent ducts that connect the testis to the epididymis, and identified cell-type specific differences. We found that efferent duct ciliary beating plays an important role for male fertility. However, research focussing on male infertility due to ODA defects in sperm and other types of motile cilia, such as efferent duct cilia, is just an emerging field and knowledge remains limited. Within this proposal we therefore aim I. to further characterize ODA complexes in human sperm flagella and efferent duct cilia, II. identify underlying genetic defects and pathogenic mechanisms leading to male infertility responsible for ODA defects. We will recruit probands who will undergo detailed clinical examination and diagnostic work up for fertility/sperm function and/or PCD. Proteomic approaches will be used to identify novel components of sperm ODA complexes and next generation sequencing approaches will aid identification of genetic defects responsible for male infertility and/or PCD. Moreover, using a mouse model, we will study in detail the role of efferent duct cilia motility for male fertility. A comprehensive genotype/phenotype correlation will finally lead to a better understanding of sperm flagella biology aiding current diagnostic tools related to male infertility and improving genetic testing and counselling.