X chromosome inactivation does not define the development of premature ovarian failure in fragile X premutation carriers

Abstract

Since only 20% of female fragile X premutation carriers develop premature ovarian failure (POF, i.e., amenorrhea before age of 40 years), and since X chromosome inactivation (XCI) determines the phenotypic severity of full mutation women, we reasoned that the development of POF in fragile X premutation carriers could be due to skewed XCI (XCI ratio >80:20). To determine inactivation ratios and activities of the premutations, inactivation patterns were assessed in peripheral blood samples from 101 fragile X premutation carriers (mean age 47.1 years, range 12-72) through analysis of the AR and FMR1 loci, respectively. In addition, AR inactivation patterns were assessed in peripheral blood samples from 25 women with idiopathic POF (mean age 31.7 years, range 19-48). We addressed the association between age and skewed XCI because older women are prone to XCI skewness. The median XCI ratios were 68% for premutation carriers with POF (N = 37), 67% for premutation carriers without POF (N = 64) and 61% for women with idiopathic POF (N = 25). The incidence of skewing was similar in all groups, that is, 7 of 37 (18.9%) in premutation carriers with POF, 11 of 64 (17.2%) in premutation carriers without POF, and 3 of 25 (12%) in women with idiopathic POF. There was good concordance between inactivation ratios at the two loci tested in 62 premutation carriers (intraclass correlation coefficient = 0.86; P < 0.01). No age-specific skewing was observed. Skewed XCI and activity of the premutation are not associated with POF in fragile X premutation carriers.

Ovarian Abnormalities in a Mouse Model of Fragile X Primary Ovarian Insufficiency

“…In some cohorts studied, such alleles are associated with the highest risk of FXPOI (Spath et al 2011). Even in cohorts where such alleles are not associated with the very highest risk, the risk of FXPOI remains high (Spath et al 2010). Thus, although 130 repeat alleles are less prevalent than smaller alleles, this allele size might allow us to see pathology in animals with a much shorter reproductive life span than humans.…”

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study

“…22,23 Differences in the incidence rates of expanded CGG repeats between fertile and infertile women were assessed using χ 2 analysis. To account for the potential effects of confounding factors, such as age, and the concentrations of FSH, AMH, and inhibin B, multiple regression analysis was performed with the data collected among the infertile women with still ongoing menstrual cycles and confirmed using Spearman rank analysis.…”

Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI)

“…Second, skewed XCI may play a role in modifying the risk or severity of FXPOI, as FMR1 is located on the X chromosome. However, no study has found evidence for skewed XCI based on samples from fresh blood among PM carriers with FXPOI [5,7,28-31]. Assuming that XCI in blood can be used as a proxy for the correct target tissue, one possible explanation for this observation is that the toxic effect of the PM acts during a stage in development when both X chromosomes are active.…”