Wang Xiayu, Du Qian, Li Wanqian, Zou Zhongyu, Wang Chikun, Zhou Yan, Hu Zhibin, Gu Yayun, Li Feng
State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China.
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
Biomolecules. 2025 Feb 17;15(2):297. doi: 10.3390/biom15020297.
PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs de novo DNA methylation. Herein, we identified a missense variant of (c.805 C>T p.R269W) in two infertile males. Homozygous male mice carrying the orthologous knock-in variant displayed elevated transposable element expression and aberrant gene expression during the first wave of spermatogenesis, despite exhibiting normal sperm counts and morphology. Mechanistically, the mutated site altered the piRNA-binding ability of PIWIL4 and led to the derepression of endogenous LINE-1 elements. In summary, we identified a piRNA binding mutation in PIWIL4 that may be involved in human nonobstructive azoospermia.
PIWI相互作用RNA（piRNA）是一类小的非编码RNA，几乎只在生殖细胞中表达，以沉默有害的转座子从而维持基因组稳定性。PIWIL4由其相关的piRNA引导至转座元件，在那里它招募DNA甲基化装置并指导从头DNA甲基化。在此，我们在两名不育男性中鉴定出一个错义变体（c.805 C>T p.R269W）。携带直系同源敲入变体的纯合雄性小鼠在精子发生的第一波过程中表现出转座元件表达升高和基因表达异常，尽管精子数量和形态正常。从机制上讲，突变位点改变了PIWIL4与piRNA的结合能力，并导致内源性LINE-1元件的去抑制。总之，我们在PIWIL4中鉴定出一个可能与人类非梗阻性无精子症有关的piRNA结合突变。
