Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause

Abstract

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.1509 T > 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.

Integrated Transcriptome Analysis Reveals the Impact of Photodynamic Therapy on Cerebrovascular Endothelial Cells

“…Enrichment results implied that PDT process may participate into regulation of E2F-mediated gene transcription and further regulate expression of down-stream genes. For these genes, CDK1 is significantly up-regulated after the H 2 O 2 -induced oxidative stress by inactivating the PI3K/AKT signaling ( 38 ); CCNA2, CDC45 , and MCM4 are downstream genes of cyclin-dependent kinase inhibitor p16 in D-galactose-induced aging in mice ( 39 ); BUB1B is involved in cell division and induces the vulnerability for oxidative stress ( 40 ); PLK1 , as the serine/threonine-protein kinase gene, also plays a major role in chromosomal instability ( 41 ) and cell cycle progression ( 42 ). These hub genes indicated that low-dose PDT intervention induces may participate into regulation of cell cycle-related pathways.…”

Identification and Validation of the Diagnostic Characteristic Genes of Ovarian Cancer by Bioinformatics and Machine Learning

“…BUB1B variants cause ovarian insufficiency and early menopause. Several studies have shown that highly elevated BUB1B is associated with high OC cell proliferation and poor clinical prognosis ( Feng et al, 2019 ; Chen et al, 2020 ). Folate receptor 1 (FOLR1) is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, enriched in oocytes of primary, secondary, and tertiary follicles as well as in surrounding granulosa cells.…”

Weighted Gene Correlation Network Analysis Applied to Identify the Immune Cell-related Hub Genes in ANCA Nephritis

“…Loss of spindle detection sites and a doubling of severe chromosome separation defects proved to be associated with BUB1B inactivation [40]. BUB1B mutated, resulting in reduced BUB1B expression, increased brittleness of antioxidant stress, and premature ovarian failure [41].…”