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Comment |
Hippo signaling in the ovary and polycystic ovarian syndrome. Maas K et al. (2018) To provide a commentary on our understanding of the role that the Hippo signaling pathway may play in patients with polycystic ovarian syndrome (PCOS) and how this understanding may impact the diagnosis of PCOS. We assessed publications discussing the role of the Hippo signaling pathway in the ovary. In particular, we discuss how Hippo signaling disruption after ovarian fragmentation, combined with treating ovarian fragments with phosphatase and tensin homolog (PTEN) inhibitors and phosphoinositide-3-kinase stimulators to augment AKT signaling, has been used in treatment of patients with primary ovarian insufficiency. Furthermore, we discuss our own data on variations in Hippo signaling pathway gene expression in cumulus cells isolated from women undergoing IVF with a previous diagnosis of PCOS. Aberrant Hippo signaling in PCOS patients is likely a contributing mechanism to the multifactorial etiology of the disease. Given the challenge of discerning the underlying etiology of oligo-ovulation in some patients, especially those with normal body mass indices, and the need for customized stimulation protocols for PCOS patients who have an increased risk of over-response and higher percentage of immature oocyte yield, it is important to identify these patients prior to treatment. Hippo gene expression fingerprints could potentially be used to more accurately define patients with PCOS. Additionally, targeting this pathway with pharmacologic agents could lead to non-surgical therapeutic options for PCOS . THIS GENE IS OVEREXPRESSED IN PCOS CUMULUS CELLS.//////////////////
Lats1 Deletion Causes Increased Germ Cell Apoptosis and Follicular Cysts in Mouse Ovaries. Sun T et al. (2015) The hippo signaling pathway is essential for regulating proliferation and apoptosis in mammalian cells. The LATS1 kinase is a core member of the hippo signaling pathway that phosphorylates and inactivates the transcriptional co-activators YAP1 and WWTR1. Deletion of Lats1 results in low neonate survival and ovarian stromal tumors in surviving adults, but the effects of Lats1 on early follicular development are not understood. Here, the expression of hippo pathway components were including Wwtr1, Stk4, Stk3, Lats2 and Yap1 transcripts were decreased by 50% in mouse ovaries between 2 and 8 days of age while expression was maintained from 8 days to 21 days and after priming with eCG. LATS1, LATS2, and MOB1B were localized to both germ and somatic cells of primordial to antral follicles. Interestingly, YAP1 was predominantly cytoplasmic, while WWTR1 was nuclear in oocytes and somatic cells. Deletion of Lats1 caused an increase in germ cell apoptosis from 1.7% in control ovaries to 3.6% in Lats1 mutant ovaries and a 58% and 32% decrease in primordial and activated follicle numbers in cultured mutant ovaries. Surprisingly, there was an increase in Bmp15, but not Gdf9, Figla, Nobox transcripts or somatic-specific transcripts Amh and Wnt4 in cultured Lats1 mutant ovaries. Lastly, Lats1 mutant ovaries developed ovarian cysts at a higher frequency (43%) compared to heterozygous (24%) and control ovaries (8%). The results show that the hippo pathway is active in ovarian follicles and that LATS1 is required to maintain the pool of germ cells and primordial follicles.//////////////////
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Mutations |
2 mutations
Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1. Hossain Z et al. (2007) Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1-/- mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for bone development, Wwtr1-/- mice show only minor skeletal defects. However, Wwtr1-/- animals present with renal cysts that lead to end-stage renal disease. Cysts predominantly originate from the dilation of Bowman's spaces and atrophy of glomerular tufts, reminiscent of glomerulocystic kidney disease in humans. A smaller fraction of cysts is derived from tubules, in particular the collecting duct (CD). The corticomedullary accumulation of cysts also shows similarities with nephronophthisis. Cells lining the cysts carry fewer and shorter cilia and the expression of several genes associated with glomerulocystic kidney disease (Ofd1 and Tsc1) or encoding proteins involved in cilia structure and/or function (Tg737, Kif3a, and Dctn5) is decreased in Wwtr1-/- kidneys. The loss of cilia integrity and the down-regulation of Dctn5, Kif3a, Pkhd1 and Ofd1 mRNA expression can be recapitulated in a renal CD epithelial cell line, mIMCD3, by reducing Wwtr1 protein levels using siRNA. Thus, Wwtr1 is critical for the integrity of renal cilia and its absence in mice leads to the development of renal cysts, indicating that Wwtr1 may represent a candidate gene for polycystic kidney disease in humans.Male and female Wwtr1-null mice were fertile, but litter size was reduced.//////////////////
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: A genome-wide association study of polycystic ovary syndrome identified from electronic health records. Zhang Y et al. (2020) Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies. To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study. We developed a polycystic ovary syndrome phenotyping algorithm based on the Rotterdam criteria and applied it to three electronic health records-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual genome-wide association study using the Geisinger's MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1x10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed effect model was adopted for meta-analysis. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to characterize protein-protein interaction network. Using the same algorithm based on the Rotterdam criteria, we identified 2,995 patients with polycystic ovary syndrome and 53,599 population controls in total (2,742 cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). We identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8x10-8) located near SOD2. Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52,2.86], P=8.45x10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 SNPs with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, while rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using STRING to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1 which has been previously associated with polycystic ovary syndrome. Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4, and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome-gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome.//////////////////
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