From DNA replication and repair to hormonal regulation

Primary ovarian insufficiency greatly influences a woman’s fertility potential and her overall health. The condition affects about 1–2 % of women and in most cases, the cause is undefined. Primary ovarian insufficiency (POI) may be caused by any process that results in dysfunction or depletion of ovarian follicles, reducing the number of oocytes within the ovary. The tendency for POI to run in families implies a strong genetic component underlying the condition. The most common single gene mutation to cause POI is the premutation of the fragile-X mental retardation gene 1 (FMR1), located on Xq27.3. Many other candidate genes have been suggested to play a role in the POI etiology, with mutations identified in genes involving follicle function and oogenesis, such as FOXL2, BMP15, NR5A1, Inhibin A, LHR, FSHR and the phenotype. In addition, variations in genes involved in meiosis and DNA repair have been hypothesized to affect the normal process of follicle formation and diminish ovarian reserve resulting in infertility. An alternative approach to identify novel POI candidate genes is the genome-wide analysis and we also report on a few studies that might have identified novel susceptibility genes for POI. High genetic heterogeneity of Premature Ovarian Insufficiency From DNA replication and repair to hormonal regulation Gouri Mukerjee, PhD and Ruslan Dorfman PhD Disclosure Statement: Gouri Mukerjee and Ruslan Dorfman are employed by Geneyouin, a company that offers genetic screening testing. Introduction A woman’s ovary has several million potential oocytes at around five months of gestational age. These are held in a quiescent state until required for ovulation, years later. Most of these potential oocytes are destroyed by the body before birth presumably as part of a quality control mechanism. Between infancy and the age of 40 years, the potential oocytes are gradually reduced from approximately one million to 10,000 in each ovary and around the age of 40, the process of egg destruction accelerates with normal aging. Unfortunately, some women can experience irregular menstrual cycles and stop producing oocytes in their early 30’s leading to the condition called Premature Ovarian Insufficiency (POI). Genetic analysis has identified aberrations in several biological pathways that can result in this condition. This review summarizes the evidence for involvement of multiple developmental genes, as well as highlights the role of known oncogenes in POI.