Yang Xiaotao, Shi Xiangrui, Wang Jing, Guo Jingying, Huang Yinhu, Tang Pan, Zhao Yu, Li Yanxi, Liu Wei, Zhang Qinghua
Reproductive Medicine Center, Daping Hospital, Army Medical University, Chongqing, 400042, China.
Institute of Immunology, Army Medical University, Chongqing, 400038, China.
Int J Med Sci. 2025 Jun 23;22(12):3132-3141. doi: 10.7150/ijms.109085. eCollection 2025.
PATL2, an RNA-binding protein and a translational repressor, plays a crucial role in maintaining mRNA homeostasis during female gametogenesis and early development of embryos. Rare pathogenic variants of its encoding gene have been implicated as causative factors for oocyte, zygote, and embryo maturation arrest (OZEMA), which results in female primary infertility and failed IVF or ICSI attempts. In this study, we identified multiple 2 variants carried by three patients from two unrelated families: compound heterozygous missense variants comprising novel c.1373T>C (p.I458T), and reported c.877G>T (p.D293Y); unprecedented homozygous missense variants of recurrent c.839G>A (p.R280Q). Molecular dynamics simulations revealed that variants I458T and D293Y severely damaged structural integrity of the PATL2 protein, strongly suggesting a more pronounced functional impairment than the other variant, R280Q. These computational results are in a good consistency with the corresponding clinical phenotypes and offer a plausible explanation for previously observed decrease of protein abundancy associated with the reported variants in 2. Our findings provide more insights into the significant impacts of both novel and recurrent 2 variants on female infertility and failed assisted reproduction.
PATL2是一种RNA结合蛋白和翻译抑制因子，在雌性配子发生和胚胎早期发育过程中维持mRNA稳态方面发挥着关键作用。其编码基因的罕见致病变异被认为是卵母细胞、受精卵和胚胎成熟停滞（OZEMA）的致病因素，这会导致女性原发性不孕以及体外受精或卵胞浆内单精子注射尝试失败。在本研究中，我们在来自两个无关家庭的三名患者中鉴定出多个PATL2变异：复合杂合错义变异，包括新的c.1373T>C（p.I458T）和已报道的c.877G>T（p.D293Y）；反复出现的c.839G>A（p.R280Q）的前所未有的纯合错义变异。分子动力学模拟显示，I458T和D293Y变异严重破坏了PATL2蛋白的结构完整性，强烈表明其功能损害比另一个变异R280Q更明显。这些计算结果与相应的临床表型高度一致，并为先前观察到的与报道的PATL2变异相关的蛋白质丰度降低提供了合理的解释。我们的研究结果为新的和反复出现的PATL2变异对女性不孕和辅助生殖失败的重大影响提供了更多见解。
