Yang Menglei, Hussain Hafiz Muhammad Jafar, Khan Manan, Muhammad Zubair, Zhou Jianteng, Ma Ao, Huang Xiongheng, Ye Jingwei, Chen Min, Zhi Aoran, Liu Tao, Khan Ranjha, Asim Ali, Shah Wasim, Zeb Aurang, Ahmad Nisar, Zhang Huan, Xu Bo, Ma Hui, Shi Qinghua, Shi Baolu
Center for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Elife. 2025 Mar 27;13:RP100350. doi: 10.7554/eLife.100350.
Asthenoteratozoospermia, a prevalent cause of male infertility, lacks a well-defined etiology. DNAH12 is a special dynein featured by the absence of a microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger sequencing on infertile patients and fertile controls from six distinct families, we unveiled six biallelic mutations in that co-segregate recessively with male infertility in the studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner dynein arms (IDAs) impairment and central pair (CP) loss in sperm flagella of the patients. Mouse models ( and ) were generated and recapitulated the reproductive defects in the patients. Noteworthy, DNAH12 deficiency did not show effects on cilium organization and function. Mechanistically, DNAH12 was confirmed to interact with two other IDA components DNALI1 and DNAH1, while disruption of DNAH12 leads to failed recruitment of DNALI1 and DNAH1 to IDAs and compromised sperm development. Furthermore, DNAH12 also interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate CP stability. Moreover, the infertility of mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. Collectively, DNAH12 plays a crucial role in the proper organization of axoneme in sperm flagella, but not cilia, by recruiting DNAH1 and DNALI1 in both humans and mice. These findings expand our comprehension of dynein component assembly in flagella and cilia and provide a valuable marker for genetic counseling and diagnosis of asthenoteratozoospermia in clinical practice.
弱畸精子症是男性不育的常见原因，其病因尚不明确。DNAH12是一种特殊的动力蛋白，其特点是缺乏微管结合结构域，然而，其在精子发生中的功能仍 largely 未知。通过对来自六个不同家庭的不育患者和可育对照进行全外显子测序及后续的桑格测序等综合基因分析，我们在 中发现了六个双等位基因突变，这些突变在研究的家庭中与男性不育呈隐性共分离。透射电子显微镜（TEM）显示患者精子鞭毛存在明显的轴丝异常，包括内动力蛋白臂（IDAs）损伤和中心对（CP）缺失。构建了小鼠模型（ 和 ）并重现了患者的生殖缺陷。值得注意的是，DNAH12缺乏对纤毛的组织和功能没有影响。从机制上讲，已证实DNAH12与另外两个IDA成分DNALI1和DNAH1相互作用，而DNAH12的破坏会导致DNALI1和DNAH1无法募集到IDAs，从而损害精子发育。此外，DNAH12还与放射辐条头部蛋白RSPH1、RSPH9和DNAJB13相互作用以调节CP稳定性。此外， 通过胞浆内精子注射（ICSI）治疗可克服小鼠的不育症。总体而言，DNAH12通过在人类和小鼠中募集DNAH1和DNALI1，在精子鞭毛而非纤毛的轴丝正确组织中发挥关键作用。这些发现扩展了我们对鞭毛和纤毛中动力蛋白成分组装的理解，并为临床实践中弱畸精子症的遗传咨询和诊断提供了有价值的标志物。
