Translocations/genes Associated With Premature Ovarian F

大约1-3%的女性经历了提前绝经，要么从未经历过月经初潮，要么在35岁左右就停止月经，而不是达到50岁左右的标准生育寿命。这种早发性“卵巢早衰（POF）”的一小部分是遗传的。3号染色体上的单个位点涉及几个家族和几个孤立的个体，其易位或缺失会中断该区域的DNA。与G. Pilia博士的团队合作，我们分离出了突变导致POF的基因FOXL2，并正在分析其功能；它似乎起着变阻器的作用，通过其功能水平来决定卵泡的数量。目前，我们已经恢复了小鼠同源基因Foxl2，并正在通过构建该基因被破坏的动物来开发其不足的小鼠模型。X染色体上更大的易位组，以长臂的关键区域为中心，与POF有关。我们现在已经证明，基于我们构建的物理图谱，至少有35个不同的X染色体位点易位可以产生POF。我们已经开始对跨越易位断点的序列进行进一步的分子分析。其中三个已经在序列水平上进行了详细分析，其中两个位于任何基因之外，位于重复序列元素的区域。这增加了一些X易位在减数分裂期间通过中断染色体动力学而起作用的可能性，而另一些则可能通过中断参与卵泡形成或稳定性的特定基因而导致POF。为了帮助理解POF中卵泡形成和维持的失败，我们已经开始了一个辅助项目来分析正常的卵巢发育。我们正在使用15K小鼠cdna微阵列（由M. Ko博士（LG）团队开发的NIA阵列）的基因表达谱来评估参与卵巢形成的基因队列。到目前为止，我们已经比较了新生卵巢（卵泡刚刚开始形成的新生小鼠）和成熟卵巢（卵泡完全形成的小鼠）的基因表达谱。仅在出生时的卵泡细胞或新生或成熟小鼠的卵母细胞中表达的标记基因已被恢复用于进一步的功能研究。使用正在构建的Foxl2被破坏的小鼠模型，这些基因将与在遗传性POF中功能受到严重影响的基因一起进行分析。在该模型中，将通过确定Foxl2控制下的靶基因来评估程序化协调基因功能的中断点。

About 1-3% of all women undergo precocious menopause, either never going through menarche or stopping menstruation by the mid-30's, rather than reaching the standard reproductive lifespan of about 50. A fraction of such instances of early-onset "premature ovarian failure (POF)" is genetic. A single locus on chromosome 3 is implicated in several families and in several isolated individuals with translocations or deletions that interrupt the DNA in that region. In collaboration with the group of Dr. G. Pilia, we have isolated the gene, FOXL2, in which mutations cause POF, and are analyzing its function; it appears to function as a rheostat, determining the number of follicles by the level of its function. Currently, we have recovered the mouse orthologue, Foxl2, and are developing a mouse model for its insufficiency by constructing animals in which the gene is disrupted. A much larger group of translocations on the X chromosome, centering on a critical region of the long arm, have been associated with POF. We have now shown that based on the physical map we had constructed, there are at least 35 distinct X chromosome loci at which translocations can produce POF. We have begun further molecular analyses of the sequences spanning translocation breakpoints. Three have been analyzed in detail at the sequence level, and two of these fall outside of any gene, in regions of repetitive sequence elements. This increases the possibility that some X translocations act by interrupting chromosome dynamics during meiosis, whereas others may cause POF by the interruption of specific genes involved in follicle formation or stability. To help understand the failure of follicle formation and maintenance in POF, we have begun an auxiliary project to analyze normal ovarian development. We are using gene expression profiling on microarrays of 15K mouse cDNAs (the NIA array developed by the group of Dr. M. Ko (LG)) to assess the gene cohorts involved in ovary formation. We have thus far compared the profile of genes expressed in nascent ovary, from newborn mice in which ovarian follicles are just starting to be formed, with mature ovary, in which follicles are fully formed. Marker genes expressed in follicle cells only at birth, or in oocytes of nascent or in mature mice have been recovered for further functional studies. These will be analyzed along with genes whose function is sharply affected in hereditary POF, using the mouse model that is under construction with Foxl2 disrupted. In that model, the point of interruption of programmed, coordinated gene function will be assessed by determining the target genes under the control of Foxl2.