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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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Autores principales: Chu, Kun, He, Yi, Li, Ziyuan, Jiang, Zhongxin, Wang, Liang, Ji, Yixuan, Wang, Xiang, Pang, Wenjuan, Sun, Ningxia, Yang, Fu, Li, Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640088/
https://www.ncbi.nlm.nih.gov/pubmed/34868246
http://dx.doi.org/10.3389/fgene.2021.764160
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author Chu, Kun
He, Yi
Li, Ziyuan
Jiang, Zhongxin
Wang, Liang
Ji, Yixuan
Wang, Xiang
Pang, Wenjuan
Sun, Ningxia
Yang, Fu
Li, Wen
author_facet Chu, Kun
He, Yi
Li, Ziyuan
Jiang, Zhongxin
Wang, Liang
Ji, Yixuan
Wang, Xiang
Pang, Wenjuan
Sun, Ningxia
Yang, Fu
Li, Wen
author_sort Chu, Kun
collection PubMed
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.
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spelling pubmed-86400882021-12-04 Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary Chu, Kun He, Yi Li, Ziyuan Jiang, Zhongxin Wang, Liang Ji, Yixuan Wang, Xiang Pang, Wenjuan Sun, Ningxia Yang, Fu Li, Wen Front Genet Genetics 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. Frontiers Media S.A. 2021-11-19 /pmc/articles/PMC8640088/ /pubmed/34868246 http://dx.doi.org/10.3389/fgene.2021.764160 Text en Copyright © 2021 Chu, He, Li, Jiang, Wang, Ji, Wang, Pang, Sun, Yang and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Chu, Kun
He, Yi
Li, Ziyuan
Jiang, Zhongxin
Wang, Liang
Ji, Yixuan
Wang, Xiang
Pang, Wenjuan
Sun, Ningxia
Yang, Fu
Li, Wen
Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary
title 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_short 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
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640088/
https://www.ncbi.nlm.nih.gov/pubmed/34868246
http://dx.doi.org/10.3389/fgene.2021.764160
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