ESPE Abstracts (2022) 95 P1-179

1Faculty of Medicine, The Hebrew University, Jerusalem, Israel; 2Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel; 3Pediatric Endocrinology and Diabetes Institute, Shamir Medical Center, tzrifin, Israel; 4The Alexander Silberman Institute of Life Science, The Hebrew University, Jerusalem, Israel; 5Division of Pediatric Endocrinology, Hadassah Medical Center, Jerusalem, Israel

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.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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