DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis.

Erica Boiman Johnstone, Bushra Gorsi, Emily Coelho, Barry Moore, Ashley M Farr, Amber R Cooper, Elaine R Mardis, Aleksander Rajkovic, Clement Y Chow, Mark Yandell, Corrine K Welt

The Journal of clinical endocrinology and metabolism 2023 Aug 18

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A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI). We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea. The study was an observational study. Subjects were recruited at an academic institution. Subjects were sisters with primary amenorrhea caused by POI and their parents. Additional subjects included women with POI analyzed previously (n = 291). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). We performed whole exome sequencing, and data were analyzed using the Pedigree Variant Annotation, Analysis and Search Tool, which identifies genes harboring pathogenic variants in families. We performed functional studies in a Drosophila melanogaster model. Genes with rare pathogenic variants were identified. The sisters carried compound heterozygous variants in DIS3. The sisters did not carry additional rare variants that were absent in publicly available datasets. DIS3 knockdown in the ovary of D. melanogaster resulted in lack of oocyte production and severe infertility. Compound heterozygous variants in highly conserved amino acids in DIS3 and failure of oocyte production in a functional model suggest that mutations in DIS3 cause POI. DIS3 is a 3' to 5' exoribonuclease that is the catalytic subunit of the exosome involved in RNA degradation and metabolism in the nucleus. The findings provide further evidence that mutations in genes important for transcription and translation are associated with POI. © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Erica Boiman Johnstone, Bushra Gorsi, Emily Coelho, Barry Moore, Ashley M Farr, Amber R Cooper, Elaine R Mardis, Aleksander Rajkovic, Clement Y Chow, Mark Yandell, Corrine K Welt. DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis. The Journal of clinical endocrinology and metabolism. 2023 Aug 18;108(9):2330-2335