ESPE2021 ePoster Category 2 Sex differentiation, gonads and gynaecology or sex endocrinology (52 abstracts)
ZSWIM7 is associated with human female meiosis and familial primary ovarian insufficiency
Sinéad M McGlacken-Byrne 1,2 , Polona Le Quesne Stabej 3,4 , Ignacio Del Valle Torres 1 , Louise Ocaka 3 , Andrey Gagunashvili 3 , Berta Crespo 5 , Nadjeda Moreno 5 , Chela James 3 , Chiara Bacchelli 3 , Mehul Dattani 1 , Hywel J Williams 6 , Dan Kelberman 3 , John C Achermann 1 & Gerard S Conway 2
1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 2Institute for Women's Health, University College London, London, United Kingdom; 3GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 4Department of Molecular Medicine and Pathology, University of Auckland, Auckland, United Kingdom; 5Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 6Division of Cancer and Genetics, Genetic and Genomic Medicine, Cardiff University, Cardiff, United Kingdom
Background: Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. In approximately 10% of cases, POI presents early with absent puberty or primary amenorrhoea. A genetic cause for POI can be found in up to 30% of women. Identified genes often relate to the complex biological processes occurring in fetal life which underpin normal ovary development and function in later adulthood.
Objective: We aimed to identify the genetic mechanism underlying early-onset POI in two sisters.
Methods: Exome sequencing and filtering using an autosomal recessive model was performed in the two affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage (CS) 22/23, 9 weeks post conception (wpc), 11wpc, 15/16wpc, 19/20wpc) and in adult tissue.
Results: The two sisters were from a consanguineous pedigree and presented with absent puberty and primary amenorrhoea. A diagnosis of POI was made on the basis of elevated FSH (94.8IU/l; 77.8IU/l), 46,XX karyotype, small ovaries on imaging, and no other obvious aetiology. Exome sequencing revealed only one homozygous variant co-segregating with the POI phenotype: a stop gain mutation in ZSWIM7, NM_001042697.2:c.173C>G, p.Ser58*. This variant is predicted to result in nonsense mediated decay and loss of the key zinc finger SWIM protein domain, precluding further functional studies. Zswim7 is involved in homologous DNA repair during meiosis in mice. qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16wpc ovary compared to testis, corresponding to peak meiosis in the fetal ovary. ZSWIM7 was expressed in both the adult ovary and testis. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes known to be important for meiosis prophase I and which have been previously implicated in the pathogenesis of POI, including MEIOB-BRCA2, STAG3, and RAD51.
Conclusions: Disruption of ZSWIM7 is associated with human meiosis and POI and can present with absent puberty. ZSWIM7 is likely to be important for homologous recombination with roles in meiotic and potentially non-meiotic recombinational DNA repair pathways. These findings expand the number of genes associated with POI and demonstrate that a mechanistic understanding of POI can be gained from considering meiotic genes as functional partners.
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