Chu Kun, He Yi, Li Ziyuan, Jiang Zhongxin, Wang Liang, Ji Yixuan, Wang Xiang, Pang Wenjuan, Sun Ningxia, Yang Fu, Li Wen
Center of Reproductive Medicine, Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Obstetrics and Gynecology, the PLA Rocket Force Characteristic Medical Center, Beijing, China.
Front Genet. 2021 Nov 19;12:764160. doi: 10.3389/fgene.2021.764160. eCollection 2021.
Premature ovarian insufficiency (POI) affects about 1% of women under 40 years and leads most often to definitive infertility with adverse health outcomes. Genetic factor has been reported to play an important role in POI. However, the genetic etiology remains unknown in the majority of the POI patients. Whole-exome sequencing and variant analysis were carried out in a POI pedigree. studies of the wild-type and mutant proteins were conducted in primary granulosa cells (GCs) and granulosa cell line. The result showed that the patients carried compound heterozygous nonsynonymous mutations (c.245C > T and c.181C > G) in gene, which were identified to be transmitted from their parents. The two variants were assessed to affect residues that were conserved across different species examined, and were predicted to be deleterious by software predictions. Protein structure predicting result indicated that the two variants could alter their interactions with surrounding residues, which may change the internal structure of the LAT protein. Moreover, LAT protein expression in GCs was demonstrated for the first time, and further functional assays suggested that this mutation could reduce LAT expression and influence GC survival, which may contribute to the etiology of POI. In summary, we detect novel pathogenic variants in a POI pedigree and report for the first time that LAT is present and functional in the GCs of the ovary. Our findings not only shed new light on the role of LAT in GCs, but also broaden the spectrum of genetic causes of POI.
卵巢早衰（POI）影响约1%的40岁以下女性，最常导致永久性不孕并伴有不良健康后果。据报道，遗传因素在POI中起重要作用。然而，大多数POI患者的遗传病因仍不清楚。对一个POI家系进行了全外显子组测序和变异分析。在原代颗粒细胞（GCs）和颗粒细胞系中对野生型和突变型蛋白进行了研究。结果显示，患者在 基因中携带复合杂合非同义突变（c.245C>T和c.181C>G），这些突变被确定是从其父母遗传而来的。评估这两个变异影响了在所检测的不同物种中保守的残基，并通过软件预测被认为是有害的。蛋白质结构预测结果表明，这两个变异可能改变它们与周围残基的相互作用，这可能会改变LAT蛋白的内部结构。此外，首次在GCs中证实了LAT蛋白的表达，进一步的功能分析表明，这种突变可能会降低LAT的表达并影响GCs的存活，这可能有助于POI的病因学研究。总之，我们在一个POI家系中检测到新的致病变异，并首次报道LAT在卵巢GCs中存在并具有功能。我们的发现不仅为LAT在GCs中的作用提供了新的线索，也拓宽了POI遗传病因的范围。
