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

Up to one-tenth of women experience miscarriage in their lifetime. Embryonic aneuploidy is a leading cause of infertility, miscarrage and congenital defects. Here, we identify loss-of-function variants of ELL3, a gene encoding a transcription elongation factor, from couples experienced consecutive early spontaneous miscarriages due to embryonic aneuploidy. Maternal ELL3 knockout leads to oocyte aneuploidy. Furthermore, we found 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. Biochemically, ELL3 competes with TPX2 to interact with the microtubule motor KIF11, promoting its ATP utilization. Live imaging analysis shows that ELL3 is essential for promoting spindle elongation rate and driving chromosome movement. Our findings demonstrate that ELL3 loss-of-function variations could lead to oocyte aneuploidy and early miscarriage. Overall design: To rule out the effect of transcription on meiosis, we performed transcriptomic analyses on Ctrl and Ell3 KD GV oocytes.Female mice were intraperitoneally injected with 7.5?IU PMSG and humanely euthanized after 48?h to collect oocytes at the GV stage. 2 sets of samples were collected for each group (5 oocytes per sample) in lysis buffer. GV oocytes was carried out using a protocol for SMART-seq2.