Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice

作者：Menglei Yang, Hafiz Muhammad Jafar Hussain, Manan Khan, Muhammad Zubair, Jianteng Zhou, Ao Ma, Xiongheng Huang, Jingwei Ye, Min Chen, Aoran Zhi, Tao Liu, Ranjha Khan, Asim Ali, Wasim Shah, Aurang Zeb, Nisar Ahmad, Huan Zhang, Bo Xu, Hui Ma, Qinghua Shi, Baolu Shi · 发表于：eLife · 年份：2025 · DOI：10.7554/elife.100350.3 · 被引用次数：13 · 研究领域：CRISPR and Genetic Engineering、Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities、Epigenetics and DNA Methylation

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 DNAH12 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 ( Dnah12 -/- and Dnah12 mut/mut ) 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 Dnah12 -/- 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 ...