Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Am J Med Genet A. 2010 Feb;152A(2):387-93. doi: 10.1002/ajmg.a.33243.
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.
由于只有 20%的女性脆性 X 前突变携带者会发展为卵巢早衰（即 40 岁之前闭经），并且由于 X 染色体失活（XCI）决定了全突变女性的表型严重程度，我们推断脆性 X 前突变携带者发生卵巢早衰可能是由于 XCI 偏斜（XCI 比>80:20）。为了确定前突变的失活比和活性，我们通过分别分析 AR 和 FMR1 基因座，评估了 101 名脆性 X 前突变携带者（平均年龄 47.1 岁，范围 12-72 岁）外周血样本中的失活模式。此外，我们还评估了 25 名特发性卵巢早衰女性（平均年龄 31.7 岁，范围 19-48 岁）外周血样本中的 AR 失活模式。我们研究了年龄与 XCI 偏斜之间的关系，因为年龄较大的女性更容易发生 XCI 偏斜。前突变携带者伴有 POF（N=37）的中位数 XCI 比为 68%，前突变携带者不伴有 POF（N=64）的中位数 XCI 比为 67%，特发性 POF 女性（N=25）的中位数 XCI 比为 61%。所有组的偏斜发生率相似，即伴有 POF 的前突变携带者中有 7 例（18.9%），不伴有 POF 的前突变携带者中有 11 例（17.2%），特发性 POF 女性中有 3 例（12%）。在 62 名前突变携带者中，两个测试的失活比之间具有良好的一致性（组内相关系数=0.86；P<0.01）。未观察到年龄特异性偏斜。脆性 X 前突变携带者中，XCI 偏斜和前突变的活性与 POF 无关。
