PDF(Pubmed)
Abstract：
Inner dynein arms (IDAs) are formed from a protein complex that is essential for appropriate flagellar bending and beating. IDA defects have previously been linked to the incidence of asthenozoospermia (AZS) and male infertility. The testes-enriched ZMYND12 protein is homologous with an IDA component identified in Chlamydomonas. ZMYND12 deficiency has previously been tied to infertility in males, yet the underlying mechanism remains uncertain. Here, a CRISPR/Cas9 approach was employed to generate Zmynd12 knockout (Zmynd12-/-) mice. These Zmynd12-/- mice exhibited significant male subfertility, reduced sperm motile velocity, and impaired capacitation. Through a combination of co-immunoprecipitation and mass spectrometry, ZMYND12 was found to interact with TTC29 and PRKACA. Decreases in the levels of PRKACA were evident in the sperm of these Zmynd12-/- mice, suggesting that this change may account for the observed drop in male fertility. Moreover, in a cohort of patients with AZS, one patient carrying a ZMYND12 variant was identified, expanding the known AZS-related variant spectrum. Together, these findings demonstrate that ZMYND12 is essential for flagellar beating, capacitation, and male fertility.
摘要：
内动力蛋白臂（IDAs）由蛋白质复合物形成，该复合物对于适当的鞭毛弯曲和跳动至关重要。以前，IDA缺陷与弱精子症（AZS）和男性不育的发生率有关。富含睾丸的ZMYND12蛋白与衣藻中鉴定的IDA成分同源。ZMYND12缺乏症以前与男性不育有关，然而，潜在的机制仍然不确定。这里,采用CRISPR/Cas9方法来产生Zmynd12敲除(Zmynd12-/-)小鼠。这些Zmynd12-/-小鼠表现出显著的雄性不育症，精子运动速度降低，和能力受损。通过免疫共沉淀和质谱联用,发现ZMYND12与TTC29和PRKACA相互作用。这些Zmynd12-/-小鼠的精子中PRKACA水平明显下降，表明这种变化可能是男性生育能力下降的原因。此外，在一组AZS患者中，确定了一名携带ZMYND12变体的患者，扩展已知的AZS相关变体谱。一起,这些发现表明ZMYND12对于鞭毛跳动至关重要，获能,男性生育能力。
