Biomaterial Database

Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest. 2022

Lin Zhao, and Qun Li, and Yanping Kuang, and Peng Xu, and Xiaoxi Sun, and Qingxia Meng, and Wenjing Wang, and Yang Zeng, and Biaobang Chen, and Jing Fu, and Jie Dong, and Jiawei Zhu, and Yuxi Luo, and Hao Gu, and Caihong Li, and Chunyi Li, and Ling Wu, and Xiaoyan Mao, and Huizhen Fan, and Ruyi Liu, and Zhihua Zhang, and Qiaoli Li, and Jing Du, and Lin He, and Li Jin, and Lei Wang, and Qing Sang

Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China.

The genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test. Through comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes. A total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg138∗], c.282C>A [p.Cys94∗]; c.257dup [p.Tyr86∗]; and c.180del, [p.Ser61Profs∗30]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes. By combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.

UI	MeSH Term	Description	Entries
D007247	Infertility, Female	Diminished or absent ability of a female to achieve conception.	Sterility, Female,Sterility, Postpartum,Sub-Fertility, Female,Subfertility, Female,Female Infertility,Female Sterility,Female Sub-Fertility,Female Subfertility,Postpartum Sterility,Sub Fertility, Female
D009865	Oocytes	Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM).	Ovocytes,Oocyte,Ovocyte
D009866	Oogenesis	The process of germ cell development in the female from the primordial germ cells through OOGONIA to the mature haploid ova (OVUM).	Oogeneses
D005260	Female		Females
D006367	HeLa Cells	The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for, among other things, VIRUS CULTIVATION and PRECLINICAL DRUG EVALUATION assays.	Cell, HeLa,Cells, HeLa,HeLa Cell
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000073359	Exome Sequencing	Techniques used to determine the sequences of EXONS of an organism or individual.	Complete Exome Sequencing,Complete Transcriptome Sequencing,Whole Exome Sequencing,Whole Transcriptome Sequencing,Complete Exome Sequencings,Exome Sequencing, Complete,Exome Sequencing, Whole,Exome Sequencings, Complete,Sequencing, Complete Exome,Sequencing, Complete Transcriptome,Sequencing, Exome,Sequencing, Whole Exome,Sequencing, Whole Transcriptome,Transcriptome Sequencing, Complete,Transcriptome Sequencing, Whole,Transcriptome Sequencings, Complete
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus