Primordial follicle pool depletion is the cause of primary ovarian insufficiency (POI) in most women. POI afflicts 1-4% of women, and genetics contributes as much as 70% to POI. Besides infertility, women with POI are at increased risk for osteoporosis and cardiovascular morbidity and mortality. Currently only karyotype and FMR1 pre-mutation testing are offered to women with POI. Fertility preservation is currently feasible fo women at risk for losing ovarian function, yet biomarkers capable of predicting ovarian insufficiency are lacking. We are interested in identifying genetic biomarkers that associate with POI. We have previously used animal models to identify regulators of primordial follicle depletion and associated genetic pathways. Human ovaries of reproductive age are difficult to access and study, and most of our understanding regarding follicular pool depletion and genesis derived from animal models. Others and we identified several novel genes including NOBOX, SOHLH1, SOHLH2, LHX8, FIGLA, FOXO3A, and FOXL2, and utilized transgenic animal models to show their involvement in primordial folliculogenesis. We previously identified plausible mutations in NOBOX and FIGLA genes in a subset of women with POI, which shows the relevance of genes discovered in animal models to human ovarian development and pathology. Using data from available animal models, we determined that there are currently over 400 genes implicated in ovarian insufficiency. This set of genes we call the """"""""ovariome"""""""". We propose to use whole exome sequencing on familial POI cases and available 1,000 genomes database as a control, to discover candidate pathologic variants. We will use the top 10 genes and top pathologic variants to replicate their association in 475 POI cases and 1,000 natural menopause controls to be recruited here at Magee Women's Hospital. We have also secured to genotype a second replication cohort with 500 POI cases and 1,000 controls. We will apply SNP array technology on 511 POI cases and 1,000 natural menopause controls to determine if certain genomic imbalances associate with POI. We hypothesize that pathologic mutations in the whole exome will be mutated in greater than 10% of women with ovarian insufficiency, and that a substantial number of these mutations will be located in the """"""""ovariome"""""""" set of genes. We also hypothesize that genomic imbalances detected by high-resolution arrays will be superior to conventional karyotype in identifying genomic imbalances in greater than 10% of women who suffer POI. Our proposal will define new genetic biomarkers for risk assessment of ovarian failure, will help predict women who may benefit from fertility preservation techniques, and will stimulate further basic science investigations by discovering novel pathways relevant to human POI.
Ovarian insufficiency adversely affects women's reproductive potential, psychosocial well being, bone mineralization, cardiovascular health and life span. We propose to determine genetic etiology of human ovarian failure through analyzing genomes of affected women and comparing them to appropriate controls. Identification of novel genetic markers for human ovarian insufficiency will help identify women at risk for increased medical morbidity and mortality as well as offer them interventions to preserve their reproductive options.
|Katari, Sunita; Aarabi, Mahmoud; Kintigh, Angela et al. (2018) Chromosomal instability in women with primary ovarian insufficiency. Hum Reprod 33:531-538|
|Richards, JoAnne S; Ren, Yi A; Candelaria, Nicholes et al. (2018) Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update. Endocr Rev 39:1-20|
|Ren, Yu; Diao, Feiyang; Katari, Sunita et al. (2018) Functional study of a novel missense single-nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency. Mol Genet Genomic Med 6:276-281|
|Portnoi, Marie-France; Dumargne, Marie-Charlotte; Rojo, Sandra et al. (2018) Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies. Hum Mol Genet 27:1228-1240|
|Khan, Muhammad Jaseem; Pollock, Nijole; Jiang, Huaiyang et al. (2018) X-linked ADGRG2 mutation and obstructive azoospermia in a large Pakistani family. Sci Rep 8:16280|
|Gurbuz, F; Desai, S; Diao, F et al. (2018) Novel inactivating mutations of the DCAF17 gene in American and Turkish families cause male infertility and female subfertility in the mouse model. Clin Genet 93:853-859|
|Desai, Swapna; Wood-Trageser, Michelle; Matic, Jelena et al. (2017) MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency. J Clin Endocrinol Metab 102:576-582|
|Shin, Yong-Hyun; Ren, Yu; Suzuki, Hitomi et al. (2017) Transcription factors SOHLH1 and SOHLH2 coordinate oocyte differentiation without affecting meiosis I. J Clin Invest 127:2106-2117|
|Dangle, Pankaj; Touzon, María Sol; Reyes-Múgica, Miguel et al. (2017) Female-to-male sex reversal associated with unique Xp21.2 deletion disrupting genomic regulatory architecture of the dosage-sensitive sex reversal region. J Med Genet 54:705-709|
|Rajkovic, Aleksandar; Pangas, Stephanie (2017) Ovary as a Biomarker of Health and Longevity: Insights from Genetics. Semin Reprod Med 35:231-240|
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