Loss of function of FIGNL1, a DNA damage response gene, causes human ovarian dysgenesis

Natan Florsheim, Larisa Naugolni, Fouad Zahdeh, Orit Lobel, Batel Terespolsky, Rachel Michaelson-Cohen, Merav Y. Gold, Michal Goldberg, Paul Renbaum*, Ephrat Levy-Lahad*, David Zangen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Ovarian dysgenesis (OD), an XX disorder of sex development, presents with primary amenorrhea, hypergonadotrophic hypogonadism, and infertility. In an Ashkenazi Jewish patient with OD, whole exome sequencing identified compound heterozygous frameshifts in FIGNL1, a DNA damage response (DDR) gene: c.189del and c.1519_1523del. Chromosomal breakage was significantly increased in patient cells, both spontaneously, and following mitomycin C exposure. Transfection of DYK-tagged FIGNL1 constructs in HEK293 cells showed no detectable protein in FIGNL1c.189del and truncation with reduced expression in FIGNL1c.1519_1523del (64% of wild-type [WT], P= .003). FIGNL1 forms nuclear foci increased by phleomycin treatment (20.6 ± 1.6 vs 14.8 ± 2.4, P= .02). However, mutant constructs showed reduced DYK-FIGNL1 foci formation in non-treated cells (0.8 ± 0.9 and 5.6 ± 1.5 vs 14.8 ± 2.4 in DYK-FIGNL1WT, P< .001) and no increase with phleomycin treatment. In conclusion, FIGNL1 loss of function is a newly characterized OD gene, highlighting the DDR pathway’s role in ovarian development and maintenance and suggesting chromosomal breakage as an assessment tool in XX-DSD patients.

Original languageAmerican English
Pages (from-to)K7-K14
JournalEuropean Journal of Endocrinology
Issue number3
StatePublished - 1 Sep 2023

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  • DNA damage response
  • FIGNL1
  • disorders of sex development
  • ovarian dysgenesis


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