FMR1 and the continuum of primary ovarian insufficiency

Spontaneous 46,XX primary ovarian insufficiency (POI) is a term that describes ovarian dysfunction resulting in a range of abnormalities, from infertility to early menopause as the end stage (overt POI). The most common known genetic cause of 46,XX POI is the expansion of a CGG repeat to 55 to 199 copies in the 5' untranslated region in the X-linked FMR1 gene. This "premutation" is associated with overt POI (FXPOI) in ~20% of carrier women. Greater than 200 CGG copies results in methylation of the CGG repeats and subsequent silencing of the FMR1 gene, causing fragile X syndrome. This "full" mutation is not associated with FXPOI. Even in the absence of overt FXPOI, women who carry the premutation may exhibit ovarian dysfunction along a continuum of severity. Evidence also suggests that the severity of FXPOI depends on the CGG repeat length, background modifier genes, and environmental factors (e.g., smoking). This review explores the range of ovarian dysfunction, the mechanisms behind the dysfunction, and the reasons for the variability in presentation in women who carry the FMR1 premutation. Understanding the mechanisms responsible for development of FXPOI is paramount to providing these women with the best overall health care.