A variant in human leucine-rich repeat and coiled-coil domain-containing 1 (LRRCC1) elevates meiotic aneuploidy in oocytes.

Purpose: Globally, infertility rates and the age of women conceiving are both increasing. Aneuploidy is a major cause of early miscarriage, and the incidence of egg aneuploidy increases with maternal age. However, significant variation in age-related aneuploidy rates exists, suggesting that age is not the sole determinant of aneuploid conception risk. We aim to understand what variants in the human genome could predispose a woman to egg aneuploidy at an earlier than average age. Methods: The gene encoding human LRRCC1 was fused to Gfp and cloned into an oocyte expression vector designed for in vitro transcription. Site directed mutagenesis was used to create point mutations previously identified in patients with high levels of egg aneuploidy. cRNA was microinjected into mouse oocytes to observe localization, incidence of aneuploidy, and meiotic spindle parameters. Results: LRRCC1-Gfp and all variants tested localized to mouse acentrosomal microtubule organizing centers (aMTOC). Expression of the LRRCC1 Conclusions: LRRCC1 promotes centrosome-independent spindle assembly during oocyte meiosis. Human genetic variants in LRRCC1, specifically p.H69Q, alter aMTOC clustering which causes abnormal spindle building, misaligned chromosomes and increased egg aneuploidy.