Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause
| Autor: | Shuyan Tang, Lingbo Wang, Jinsong Li, Hanni Ke, Xuezhen Luo, Qing Chen, Yingying Qin, Yanhua Wu, Feng Zhang, Xiaojun Chen, Li Jin |
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| Rok vydání: | 2020 |
| Předmět: |
Infertility
Mutation Missense Turner Syndrome Cell Cycle Proteins Biology Primary Ovarian Insufficiency Protein Serine-Threonine Kinases BUB1B Premature ovarian insufficiency Bioinformatics DNA Mitochondrial 03 medical and health sciences Mice 0302 clinical medicine Pregnancy Exome Sequencing Genetics medicine Missense mutation Animals Humans Molecular Biology Genetics (clinical) Exome sequencing 030304 developmental biology Mice Knockout 0303 health sciences 030219 obstetrics & reproductive medicine Genetic heterogeneity Female infertility General Medicine medicine.disease Pedigree Menopause Phenotype Female Follicle Stimulating Hormone Infertility Female |
| Zdroj: | Human molecular genetics. 29(16) |
| ISSN: | 1460-2083 |
| Popis: | Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25–30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/− female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders. |
| Databáze: | OpenAIRE |
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