Translocations/genes in Premature Ovarian Failure

大约1-3%的女性经历过早的更年期，要么从未经历过初潮，要么在30年代中期停止月经，而不是达到约50岁的标准生殖寿命。一小部分早发性卵巢早衰（POF）是遗传性的。3号染色体上的一个单一基因座与几个家庭和几个孤立的个体有关，这些个体具有中断该区域DNA的易位或缺失。与G博士的团队合作。我们分离出FOXL 2基因，该基因突变会导致POF和眼睑畸形，并正在分析其功能;它似乎起着变阻器的作用，通过其功能水平决定卵泡的数量。我们已经恢复了小鼠直系同源物Foxl 2，并产生了敲除以创建小鼠模型。我们开始描述由此产生的表型，它似乎模仿缺乏FOXL 2等位基因的女性的眼睑和卵巢特征。在X染色体上，以长臂的关键区域为中心的一组更大的易位与POF有关。我们已经成功地证明，根据我们构建的物理图谱，至少有35个不同的X染色体位点可以发生易位，从而导致POF。我们已经开始对跨越易位断裂点的序列进行进一步的分子分析。三个已经在序列水平上进行了详细的分析，其中两个落在任何基因之外，在重复序列元件的区域中。这增加了一些X易位通过在减数分裂期间中断染色体动力学而起作用的可能性，而另一些易位可能通过中断参与卵泡形成或稳定性的特定基因而引起POF。为了帮助理解卵巢早衰中卵泡形成和维持的失败，我们使用15 K cDNA微阵列（由M. Ko（LG）），以评估参与卵巢形成的基因群组。到目前为止，我们已经比较了在新生卵巢中表达的基因谱，来自卵泡刚刚开始形成的新生小鼠，与成熟卵巢，其中卵泡完全形成，并将它们与睾丸中表达的基因进行比较。标记基因表达的卵泡细胞只在出生时，或在卵母细胞的新生或成熟的小鼠已恢复进一步的功能研究。这些将与在遗传性POF中功能受到显著影响的基因一起进行沿着分析，使用用破坏的Foxl 2产生的小鼠模型。在该模型中，将通过确定Foxl 2控制下的靶基因来评估程序化和协调的基因功能的中断点。

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 isolated the gene, FOXL2, in which mutations cause POF and an eyelid malformation, and are analyzing its function; it appears to function as a rheostat, determining the number of follicles by the level of its function. We have recovered the mouse orthologue, Foxl2, and have generated a knockout to create a mouse model. We are beginning to characterize the resulting phenotype, which seems to mimic eyelid and ovarian features seen in women lacking one allele of FOXL2. 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 prevously 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 analyzing the normal ovarian development in mouse using 15K cDNA microarray (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 and compared them to those expressed in testes. 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 generated with disrupted Foxl2. In that model, the point of interruption of programmed and coordinated gene function will be assessed by determining the target genes under the control of Foxl2.