ESPE2022 Poster Category 1 Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (56 abstracts)
Background: Severe Ovarian Dysgenesis (OD), a rare heterogeneous XX disorder of Sex Development presents clinically with primary amenorrhea, hypergonadotrophic hypogonadism and infertility. The genetic basis of OD remains unknown in 70% of cases. To identify novel causes of OD, we study patients in which known genes have been excluded.
Methods: Whole-exome-sequencing was performed in a 14.5y old Ashkenazi Jewish, non-consanguineous origin patient, with OD. DNA damage response (DDR) was tested using MitomycinC (MMC) in chromosomal breakage assay, and analysis of ɣH2AX and DYK-Fignl1 foci in response to MMC and Phleomycin.
Results: We identified compound heterozygous frameshift deletions in FIGNL1, a DDR pathway gene: c.189delT and c.1519delTCTCA. Segregation was consistent with recessive inheritance. Western blots of DYK-tagged-FIGNL1-constructs showed no protein is produced by c.189delT, and 64% of WT (P=0.003) is produced by c.1519delTCTCA. Chromosomal breakage assays revealed significantly higher number of DNA breaks in patient-derived fibroblasts compared to control. DNA breaks increasement occurred both spontaneously (22.82±1.66 vs. 10.61±0.98 P=6X10-9) and following DNA damage induction (MMC, 5.00±0.59 vs. 2.50±0.25 P=0.003). HeLa cells transfected with DYK-tagged-FIGNL1-mutant or wild-type constructs showed overall decrease in nuclear foci (c.1519delTCTCA 5.6±1.5 vs. 14.8±0.9) and in recruitment of FIGNL1 to the nucleus in response to phleomycin (0±1.3 vs. 5.8±0.8 P=0.02) in the mutant transfected cells.
Conclusions: The novel compound heterozygous mutations in FIGNL1 are accompanied by impaired DDR and suggest that FIGNL1 loss of function is a novel genetic etiology for ovarian dysgenesis in humans. This further expands the crucial role of DDR pathway in normal ovariogenesis.
15 Sep 2022 - 17 Sep 2022