Premature ovarian failure and fragile X female premutation carriers

Abstract

The association between FMR1 premutation and ovarian dysfunction has been widely studied, and many factors such as the repeat tract size, the sequence organization of the CGG repeat tract, the parental origin of the premutation, and the FMR1 mRNA levels have been examined. X-chromosome inactivation has also been studied as a risk factor, but the reported results are inconclusive. Although some authors did not find an association with the premature ovarian failure manifestation, others suggest that the severity of FMR1 premutation-associated phenotypes may be related to this X-inactivation ratio. To evaluate the significance of skewed X-inactivation patterns among female premutated carriers, we examined and compared the X-inactivation ratios of 220 female samples from the general population and 260 female premutation carriers phenotypically unaffected or affected by premature ovarian failure. The results failed to show a direct effect of X-inactivation in the manifestation of premature ovarian failure among FMR1 premutation carriers. However, a negative correlation has been found between X-chromosome inactivation and low-medium CGG repeat size alleles. The manifestation of premature ovarian failure cannot be merely explained by the X-chromosome inactivation patterns; however, we speculate that together with other genetic factors, it might contribute.