Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary
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 pati...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:2d26211a21e24d07af5c7aac3f5918ec2021-11-19T05:55:48ZNovel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary1664-802110.3389/fgene.2021.764160https://doaj.org/article/2d26211a21e24d07af5c7aac3f5918ec2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.764160/fullhttps://doaj.org/toc/1664-8021Premature 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.Kun ChuKun ChuYi HeYi HeZiyuan LiZhongxin JiangLiang WangYixuan JiXiang WangWenjuan PangNingxia SunFu YangWen LiFrontiers Media S.A.articlegenetic variantsprimary ovarian insufficiencythe linker for the activation of T cellsgranulosa cellwhole-exome sequencinggenetic varaiantGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021) |
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genetic variants primary ovarian insufficiency the linker for the activation of T cells granulosa cell whole-exome sequencing genetic varaiant Genetics QH426-470 |
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genetic variants primary ovarian insufficiency the linker for the activation of T cells granulosa cell whole-exome sequencing genetic varaiant Genetics QH426-470 Kun Chu Kun Chu Yi He Yi He Ziyuan Li Zhongxin Jiang Liang Wang Yixuan Ji Xiang Wang Wenjuan Pang Ningxia Sun Fu Yang Wen Li Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary |
| description |
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. |
| format |
article |
| author |
Kun Chu Kun Chu Yi He Yi He Ziyuan Li Zhongxin Jiang Liang Wang Yixuan Ji Xiang Wang Wenjuan Pang Ningxia Sun Fu Yang Wen Li |
| author_facet |
Kun Chu Kun Chu Yi He Yi He Ziyuan Li Zhongxin Jiang Liang Wang Yixuan Ji Xiang Wang Wenjuan Pang Ningxia Sun Fu Yang Wen Li |
| author_sort |
Kun Chu |
| title |
Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary |
| title_short |
Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary |
| title_full |
Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary |
| title_fullStr |
Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary |
| title_full_unstemmed |
Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary |
| title_sort |
novel lat pathogenic variants in a poi family and its role in the ovary |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/2d26211a21e24d07af5c7aac3f5918ec |
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