Maternal ELL3 loss-of-function leads to oocyte aneuploidy and early miscarriage

Abstract

Up to an estimated 10% of women experience miscarriage in their lifetimes. Embryonic aneuploidy is a leading cause for miscarriage, infertility and congenital defects. Here we identify variants of ELL3, a gene encoding a transcription elongation factor, in couples who experienced consecutive early miscarriages due to embryonic aneuploidy. Maternal ELL3 knockout leads to mouse oocyte aneuploidy, subfertility and miscellaneous embryonic defects. Mechanistically, we find that ELL3 localizes to the spindle during meiosis, and that ELL3 depletion in both mouse and human oocytes increases the incidence of meiotic spindle abnormality. ELL3 coordinates with TPX2 to ensure the proper function of the microtubule motor KIF11. Live imaging analysis shows that ELL3 is paramount for promoting spindle assembly and driving chromosome movement. Together, our findings implicate maternal ELL3 deficiency in causing oocyte aneuploidy and early miscarriage. The authors show that ELL3 maintains chromosomal ploidy by promoting spindle assembly and driving chromosome movement in oocytes. Deficiency of ELL3 results in oocyte aneuploidy and may lead to early miscarriage.