Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation
Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation
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DOI：
10.1093/humrep/dei432
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发表时间：
2006-04-01
影响因子：
6.1
通讯作者：
Marozzi, A
中科院分区：
文献类型：
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作者：
Bodega, B;Bione, S;Marozzi, A
背景技术背景：试图精确定义脆性智力低下1（FMR 1）扩增范围及其对卵巢早衰（POF）表现的影响的研究部分缺乏。为此，我们评估了一个大的POF患者队列的规模，并在选定的情况下，CGG扩展的顺序。此外，POF和X-失活之间的相关性进行了调查，在FRAXA家庭。方法：通过荧光PCR，190例POF和200例对照妇女的CGG道大小;一些受试者还通过测序和FMR 1激活率进行了表征。结果与结论：我们发现POF和FMR 1前突变（范围63-163个重复）之间存在显著关联（19/190，10%，P < 1 × 10（-6）），中度扩增（范围41-58个重复）的POF携带者显著富集（9/190，4.7%，P = 0.021）。有趣的是，中间等位基因完全由CGG重复组成。此外，对三对FMR 1扩增相似且POF表型不一致的兄弟姐妹的分析表明，中间/预突变等位基因的表达与POF表现之间存在直接相关性。所获得的结果加强FMR 1扩增和POF之间的相关性，并建议卵巢功能障碍的表现可能受到CGG重复序列中断模式和X-失活的影响。
BACKGROUND: Studies attempting to precisely define the range of fragile mental retardation 1 (FMR1) expansions and its inf luence in premature ovarian failure (POF) manifestation are partially lacking. To this aim, we evaluated a large cohort of POF patients for the size and, in selected cases, for the sequence of the CGG expansion. Furthermore, the correlation between POF and X-inactivation was investigated in FRAXA families. METHODS: By fluorescent PCR, 190 POF and 200 control women were sized for the CGG tract; some subjects were also characterized by sequencing and for the FMR1 activation ratio. RESULTS AND CONCLUSION: We found a significant association (19/190, 10%, P < 1 x 10(-6)) between POF and FMR1 premutation (range 63-163 repeats) and a significant enrichment (9/190, 4.7%, P = 0.021) of POF carriers of intermediate expansions (range 41-58 repeats). Interestingly, intermediate alleles were entirely composed of CGG repeats. Furthermore, the analysis of three pairs of siblings with similar FMR1 expansions and discordant for the POF phenotype showed a direct correlation between the expression of the intermediate/premutated allele and POF manifestation. The results obtained strengthen the correlation between FMR1 expansion and POF and suggest that the manifestation of the ovarian dysfunction could be influenced both by the pattern of interruption of the CGG repeat and by X-inactivation.