P-076 Role of N-DRC complex in male fertility

Abstract

Abstract Study question There are many causes of human infertility, what’s the role of Nexin-dynein regulatory complex (N-DRC) in male fertility? Summary answer Many gene mutants in N-DRC components have been identified in infertile men, which affect the assembly of N-DRC complex and cause defects of sperm. What is known already human infertility affects 10–15% of couples, asthenozoospermia accounting for 18% of infertile men and is a common male infertility phenotype. Nexin-dynein regulatory complex (N-DRC) is a large protein complex regulating device in the flagellum and connects adjacent doublets of microtubules (DMTs). Some N-DRC components were reported to be associated with human disease, such as Primary ciliary dyskinesia (PCD). In recent years, more and more studies reported mutants in subunits of N-DRC are related to male infertility. For example, DRC1, DRC5 and DRC3 mutant were identified in patients displayed multiple morphological abnormalities of the flagella (MMAF) and obstructive azoospermia. Study design, size, duration We searched articles about N-DRC and male infertility in pumped and select research studies and the tidied up the gene mutants, gene knock out mouse modals and IVF outcomes of different N-DRC components in infertile men. Besides, we summarized the parameters of semen and ultrastructure of sperm flagella in these patients. Participants/materials, setting, methods We searched articles about N-DRC and male infertility in pumped and select research studies and the tidied up the gene mutants, gene knock out mouse modals and IVF outcomes of different N-DRC components in infertile men. Main results and the role of chance N-DRC is a highly conserved structural complex located in the axoneme of the flagellum and cilium, containing at least 11 different subunits (DRC1∼DRC11). Patients who were diagnosed as MMAF and male infertility carrying homozygous DRC1 mutants. TEM analyses of the patients’ sperm revealed the flagellar axoneme structure is disordered. A frameshift mutant of DRC5 was identified in an infertile male with asthenozoospermia, but the patient’s problem of infertility could be successfully solved by vitro Fertilization (IVF). A recent study identified two bi-allelic DRC3 frameshift variants in two unrelated patients, one patient displayed MMAF and the other present obstructive azoospermia. The sperm flagella function of DRC5 deletion mice was abrogated but flagellum ultrastructure remained normal and the mice behaved as asthenozoospermia and sterile. DRC3, DRC7 and DRC9 knockout mice exhibit MMAF and male infertility, and in DRC7 KO mice, the axoneme of sperm is disorganized and it was difficult to detect the ‘9 + 2’ microtubule structure. DRC1 mutant mice on the C57BL/6 background died before puberty, KO DRC6 in mice neither has no obvious effects on sperm motility function nor destroy the “9 + 2” arrangement of microtubules in cilia, and male mice was fertile. Limitations, reasons for caution More samples of MMAF and asthenozoospermia men to sequence N-DRC gene, and track their assisted reproductive outcomes. Wider implications of the findings The conclusions in our study uncover certain mechanism of N-DRC deficient in MMAF and asthenozoospermia phenotype, which could provide a new basis for diagnosis of male infertility. Trial registration number not applicable