Ovarian Function/Dysfunction
Session: Poster Session A
Jessica M. Stringer, PhD
Research Fellow
Women's Health and Ovarian Biology Laboratory, Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
Clayton, Victoria, Australia
Jessica M Stringer1; Stevan Novakovic2; Elissah Granger2; Caitlin Harris2; Vanessa Tsui2; Karla Hutt1; Eva R. Hoffmann3; Davis J. McCarthy2; Wayne Crismani2
1Ovarian Biology Laboratory, Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
2DNA Repair and Recombination Laboratory, St Vincent’s Institute of Medical Research, Fitzroy, Melbourne, Australia
3DNRF Centre for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Abstract Text: Fanconi anemia (FA) is a complex autosomal genetic disorder marked by bone marrow failure, birth defects, and an increased risk of cancer, all stemming from the inability to repair DNA interstrand cross-links and heightened genomic instability. Females with FA experience reduced fertility, which typically leads to early menopause, often by their early 30s. Gametogenesis is significantly disrupted in Fancm loss-of-function mice (Fancm-/-), reflecting the reproductive issues seen in humans with biallelic FANCM mutations. Despite these reproductive challenges in Fancm-/- mutants, both male and female mice are still able to produce offspring. In humans, approximately 15% of female FA patients successfully carry pregnancies to term. Notably, we can replicate this irregular and early menopause-related fertility issue in our mouse models by crossing the same Fancm-/- mutation onto two distinct mouse strains (C57BL/6J and FVB). In the C57BL/6J mouse line Fancm-/- female mice were almost completely infertile compared to wildtype controls (wildtype 10/10 had between 7-10 litters vs Fancm-/- 2/5 females had a single litter of < 5pups). However, the FVB Fancm-/- female mice have fewer litters (wildtype 4.57±1.9 vs Fancm-/- 2.44±1.0, P< 0.01) and a significant reduction in age (days) at last litter (wildtype 174.7±63.3 vs Fancm-/- 116.3±25.6, P< 0.02) compared to controls, indicative of premature menopause observed in female FA patients. When we cross the two inbred lines together we recover fertility to wildtype levels in the F1 females. However, females from subsequent generations (F3 and F4) in the Fancm-/- hybrid line had diminished litter number, size and age at last litter compared to matched wildtype controls. As Fancm-/- results in a genome-wide increase in meiotic crossover frequency, responsible for shuffling the C57BL/6J and FVB genomes, we will use whole genome sequencing of hybrid F4 parents and F5 offspring to map meiotic crossover sites and identify mutations associated with reduced fertility. This analysis will provide novel biomarkers for infertility and premature menopause relevant for FA patients and women in general.