Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan, 430030, China.
J Ovarian Res. 2024 Sep 4;17(1):180. doi: 10.1186/s13048-024-01462-9.
Pannexin1 (PANX1) is a highly glycosylated membrane channel-forming protein, which has been found to implicate in multiple physiological and pathophysiological functions. Variants in the PANX1 gene have been reported to be associated with oocyte death and recurrent in vitro fertilization failure. In this study, we identified a novel heterozygous PANX1 variant (NM_015368.4 c.410 C > T (p.Ser137Leu)) associated with the phenotype of oocyte death in a non-consanguineous family, followed by an autosomal dominant (AD) mode. We explored the molecular mechanism of the novel variant and the variant c.976_978del (p.Asn326del) that we reported previously. Both of the variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, affected ATP release and membrane electrophysiological properties, which resulted in mouse and human oocyte death in vitro. For the first time, we presented the direct evidence of the effect of the PANX1 variants on human oocyte development. Our findings expand the variant spectrum of PANX1 genes associated with oocyte death and provide new support for the genetic diagnosis of female infertility.
缝隙连接蛋白 1（PANX1）是一种高度糖基化的膜通道形成蛋白，已被发现涉及多种生理和病理生理功能。PANX1 基因的变异与卵母细胞死亡和反复体外受精失败有关。在这项研究中，我们在一个非近亲家庭中发现了一种与卵母细胞死亡表型相关的新型杂合 PANX1 变体（NM_015368.4 c.410C>T（p.Ser137Leu）），呈常染色体显性（AD）遗传模式。我们探索了新型变体和我们之前报道的变体 c.976_978del（p.Asn326del）的分子机制。这两种变体都改变了培养细胞中 PANX1 的糖基化模式，导致异常的 PANX1 通道激活，影响 ATP 释放和膜电生理特性，从而导致体外小鼠和人卵母细胞死亡。我们首次提供了 PANX1 变体对人卵母细胞发育影响的直接证据。我们的研究结果扩展了与卵母细胞死亡相关的 PANX1 基因突变谱，并为女性不孕的遗传诊断提供了新的支持。
