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

Abstract

Context: A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI).

Objective: We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea.

Design: The study was an observational study. Subjects were recruited at an academic institution.

Subjects: 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).

Intervention: 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.

Main outcome: Genes with rare pathogenic variants were identified.

Results: 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.

Conclusions: 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.

Keywords: RNA; genetics; menopause; recessive; whole exome sequencing.

Figure 1.

Pedigree of family in which 2 girls presented with POI. The girls affected with primary ovarian insufficiency are indicated with filled circles, with age indicating presentation with primary amenorrhea. Compound heterozygous variants were identified in DIS3: in-frame deletion (c.1871-1874 CCTT > C) and missense variant (c.2342G > C). The father carried c.1871-1874 CCTT > C and the mother carried c.2342G > C. Please note that the pedigree is not complete to maintain confidentiality. Electropherograms are presented for all family members who underwent sequencing.

Figure 2.

Dis3 Drosophila melanogaster ovarian phenotype. Ovary-specific knockdown of dis3 results in complete infertility (A), zero egg production (B), and small and dysgenic ovaries compared to controls (C). Note the 2 atrophic ovaries on the right side of the knockdown with some reproductive tract tissue on the left side of the structure. C, control.