Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary

Kun Chu; Yi He; Ziyuan Li; Zhongxin Jiang; Liang Wang; Yixuan Ji; Xiang Wang; Wenjuan Pang; Ningxia Sun; Fu Yang; Wen Li

doi:10.3389/fgene.2021.764160

Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary

Front Genet. 2021 Nov 19:12:764160. doi: 10.3389/fgene.2021.764160. eCollection 2021.

Authors

Kun Chu^{1

2}, Yi He^{1

3}, Ziyuan Li⁴, Zhongxin Jiang⁴, Liang Wang⁴, Yixuan Ji⁴, Xiang Wang³, Wenjuan Pang⁴, Ningxia Sun⁴, Fu Yang⁵, Wen Li¹

Affiliations

¹ 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.
² Department of Obstetrics and Gynecology, the PLA Rocket Force Characteristic Medical Center, Beijing, China.
³ Department of Obstetrics and Gynecology, No. 905 Hospital of PLA Navy, Shanghai, China.
⁴ Center of Reproductive Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China.
⁵ Department of Medical Genetics, Naval Medical University, Shanghai, China.

Abstract

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. In vitro 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 LAT 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 LAT 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.

Keywords: genetic varaiant; genetic variants; granulosa cell; primary ovarian insufficiency; the linker for the activation of T cells; whole-exome sequencing.