I-41: Genetic Causes of Premature Ovarian Failure (POF) and early Menopause

Premature ovarian failure (POF) is a heterogeneous disorder, defined as menopause under age 40 years. The prevalence is 1%; POF before age 30 years is much less common. Chromosomal causes have long been recognized - visible deletions of the X chromosome, 45,X/46,XX mosaicism, and autosomal rearrangements (balanced translocations). Toxins or iatrogenic causes (e.g., chemotherapeutic agents) are occasionally implicated; autoimmune causes exist. However, lack of explanations for most cases has led to the deduction that single gene mutations (autosomal or X-linked) must be responsible for most cases of POF. With molecular technology it is now possible to determine if a single cell is perturbed in POF. Many attractive candidate genes exist, usually based on animal models (mice). The most common single gene responsible for POF if perturbed is FMR1 (fragile X), CGG expansion explaining perhaps 5% of sporadic cases. A predictable set of genes whose perturbations cause POF are those encoding gonadotropins (FISH, LH) or their receptors (FSHR, LHR). Mutations in these gonadotropin-related genes are known but rare except for FSHR mutations in Finland. Other genes expressed during oogenesis have been interrogated by ourselves, including DNA binding proteins and transcription factors (NOBOX and LHX8), RNA binding proteins (NANOS, TGFβ family members such as GDF9), and G protein receptors (GPR3). Additional genes expressed in oocytes (AT2, KIT, NOGGIN, MIS, MISR, BAX, RFPL4), are attractive candidates. To date causative mutations have still been identified in only a few genes (NOBOX, GDF9, LDX8, BMP15) each explaining perhaps 1-2% of POF cases. However, population-specific studies are still limited, and a single mutation may prove important in certain populations like FSHR in Finland. Genome wide association studies (GWAS) are in progress and exome-sequencing planned. Clinical significance will arise from identifying POF genes. 1) Better prognosis and ovarian preservation can be offered for younger for younger family members having the same mutation; 2) Therapeutic replacement products can be envisioned to mitigate against ovarian failure.