This report describes primary ovarian insufficiency, DIS3-related, a recently described form of primary ovarian insufficiency (POI). This form of POI exhibits autosomal recessive inheritance. The DIS3 gene encodes a component of the RNA exosome complex. There is a single high-scoring ortholog in Drosophila, Dmel\Dis3, for which multiple genetic reagents have been generated including classical amorphic alleles, RNAi-targeting constructs, and overexpression constructs. Dmel\Dis3 is a low-scoring ortholog of a second human gene, DIS3L.
Ovary-specific RNAi-mediated knockdown of Dmel\Dis3 (using multiple drivers) in female flies results in complete infertility; ovaries appear small and dysgenic with no oocytes present. Knockdown of Dis3 restricted to somatic cells of the ovary results in no visible ovarian structures or germ cells; germline-specific knockdown results in small, poorly formed ovaries without detectable germ cells.
Multiple UAS constructs of human Hsap\DIS3 have been introduced into flies, including wild-type and a variant implicated in POI; see the 'Disease-Implicated Variants' table below. Co-expression of the wild-type human gene results in partial functional complementation (heterologous rescue) of the infertility phenotype of ovary-specific somatic cell knockdown of Dmel\Dis3.
When expressed in the somatic cells of the ovary, co-expression of RNAi and the human gene carrying the DIS3:p.His774Tyr variant results in a some rescue, but significantly less than that observed for the wild-type human gene. Thus, it is hypothesized that this variant acts as a hypomorph. Co-expression of RNAi and of the variant in the germline results in a level of rescue (of the less severe phenotype, see above) comparable to that observed with the wild-type human gene. These results suggest that human DIS3 may be more critical to somatic cell support of oocytes than to the germline.
[updated Mar. 2025 by FlyBase; FBrf0222196]
Primary ovarian insufficiency is a subclass of ovarian dysfunction in which the cause is within the ovary. In most cases, premature exhaustion of the resting pool of primordial follicles occurs. The main symptom is absence of regular menstrual cycles; the disorder usually leads to sterility (De Vos, et al., 2010; pubmed:20708256).
Nonsyndromic primary ovarian insufficiency, which is characterized by amenorrhea with elevated gonadotropin levels, is observed in 1% of otherwise healthy women under the age of 40 years (summary by Wang et al., 2014; pubmed:24597873). [from MIM:615724, 2021.11.14]
The cases described to date are consistent with autosomal recessive inheritance (Johnstone et al., 2023, pubmed:36869713, FBrf0257263; Kline et al., 2024, pubmed:39400047, FBrf0261420).
DIS3 encodes the putative catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts. [GeneCards, DIS3; 2025.03.10]
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human DIS3; low-scoring ortholog of human DIS3L (1 Drosophila to 2 human).
