Translocations/genes associated with Premature Ovarian Failure

大约有1%-3%的女性经历了早熟绝经，要么从未经历过月经初潮，要么在S 30岁左右停止月经，而不是达到约50岁的标准生育寿命。这种早发性“卵巢早衰(POF)”中的一小部分是遗传的。3号染色体上的一个单基因座与几个家系和几个有易位或缺失的孤立个体有关，这些易位或缺失导致该区域的DNA中断。在与G.Pilia博士的团队合作中，我们分离了导致POF的突变基因，并正在分析其功能；它似乎起到了变阻器的作用，根据其功能水平确定卵泡的数量。据报道，X染色体上有一组更大的易位，集中在长臂的一个关键区域。在这里，我们已经表明，基于我们构建的物理图谱，至少有35个不同的X染色体座位可以产生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。其中两个已经在序列水平上进行了详细的分析，其中一个属于任何基因之外的重复序列元素区域。这增加了一些X易位通过干扰减数分裂过程中的染色体动力学来发挥作用的可能性，而另一些X易位可能通过中断参与卵泡形成或稳定的特定基因而导致POF。在一个相关的项目中，我们正在使用15K小鼠cDNA微阵列(M.Ko(LG)博士小组年度报告中的NIA阵列)的基因表达谱来评估参与卵巢发育的基因队列。这些研究将与分析遗传性POF中功能受到严重影响的基因相结合，使用正在构建的3号染色体候选基因的靶向干扰的小鼠模型。

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 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. A much larger group of translocations have been reported on the X chromosome, centering on a critical region of the long arm. There we have 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. Two have been analyzed in detail at the sequence level, and one of those falls outside of any gene, in a region 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. In an associated project, we are using gene expression profiling on microarrays of 15K mouse cDNAs (the NIA array in the annual report of the group of Dr. M. Ko (LG)) to assess the gene cohorts involved in ovarian development. The studies will be combined with analyses of genes whose function is sharply affected in hereditary POF, using a mouse model that is under construction with the targeted disruption of the chromosome 3 candidate gene.