Are we Close to Solve the Mystery of Fragile X Associated Premature Ovarian Insufficiency (FXPOI) in FMR1 Premutation Carriers?

Fragile X Syndrome (FXS), the most common form of inherited mental retardation, is caused by a trinucleotide repeat expansion (CGG >200) in the 5'-untranslated region of the fragile X Mental Retardation 1 (FMR1) gene. Amplification of the CGG triplet number above the normal range (n=5-44) towards the so-called premutation status (n=55-200) is associated with increased risk for Fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) in males. Very little is known about the mechanisms leading to FXPOI. The observation that premutation carriers, both males and females, have increased FMR1 transcript levels, led researchers to suggest a similar molecular pathogenesis in both FXPOI and FXTAS. A variety of models have been proposed as the culprits of FXTAS and FXPOI: The toxic RNA gain-of-function model: This model suggests that DNA containing CGG expanded repeats leads to the formation of dynamic intranuclear long rCGG RNA aggregates that sequesters specific RNA binding proteins. Proteins such as Sam68 and DGCR8 and its partner DROSHA, directly bind to the double-stranded RNA hairpin structure of long rCGG RNA aggregates resulting in the loss of normal cell function and cell death. Repeat Associated Non-AUG initiated (RAN) translation: Due to translation of the expansion mutation, as part of a larger open-reading frame (ORF), mutant protein named polyglycine-containing protein (FMRpolyG) is expressed in neuronal cells and granulosa cells, with the consequent disruption of cellular function, leading to cell toxicity.