Glypican 3 Action in Overgrowth Syndromes

一组表型相似的人 巨人症/过度生长综合征包括一种X连锁形式， Simpson-Golabi-Behmel(SGB)综合征。尽管有一些人 类似的情况映射到11p15.5的不同座位，使 这些疾病的病因复杂，我们表明SGBs的结果 明确地由Glypical3的功能缺失突变引起 (GPC3)基因。在过去的一年里，几乎所有伟大的基因组 该基因的全长(超过600kb)已被测序并 进行了分析，并开始了对该基因的生理研究。这个 基因组DNA被证明有第二个Glypcan(GPC4)作为 下一个着丝粒基因，以及它的序列和组织分布 已经对该基因进行了比较；在两名患者中，GPC3的缺失 扩展到GPC4，但患者显然是可行的，而且有 较大的缺失没有明确的附加表型。 对启动子的研究表明，它含有初级的 转录因子位点被甲基化以关闭它在 X-失活的染色体，并且甲基化足以 关闭转录；但在几种类型的细胞中，转录失败 即使在没有甲基化的情况下，额外的转录 决定致密组织分布的因素必须包括在内 这种基因的。合作者已经证明了这种组织的特异性 将IGF2的表达模式非常紧密地重叠，并控制 IGF2功能的改变仍然是GPC3基因的一个可能作用。 对小鼠的基因作用进行更深入的分析应该是可能的 模型，该模型是由以下合作者构建的 干扰了小鼠的GPC3基因。基因敲除的小鼠显示出 以及GPC3和其他基因的相互作用， 包括IGF2生长调控途径中的那些，正在被 在合适的杂交后代中进行了测试。

A group of phenotypically similar gigantism/overgrowth syndromes include one X-linked form, Simpson-Golabi-Behmel (SGBS) syndrome. Although a number of similar conditions map to various loci in 11p15.5, making the etiology of those diseases complex, we showed that SGBS results unequivocally from loss-of- function mutations in the glypican 3 (GPC3) gene. In the last year, nearly all of the very great genomic extent of the gene (more than 600 kb) has been sequenced and analyzed, and physiological studies of the gene have begun. The genomic DNA proved to have a second glypican (GPC4) as the next centromeric gene, and the sequence and tissue distribution of that gene have been compared; in two patients, deletions in GPC3 extend into GPC4, but the patients are clearly viable, and there is no clear additional phenotype conferred by the larger deletions. Studies of the promoter have shown that it contains primary transcription factor sites that are methylated to shut it down in X-inactivated chromosomes, and that methylation is sufficient to shut off transcription; but in several types of cells transcription fails even in the absence of methylation, so that additional transcription factors must be involved in determining the tight tissue distribution of the gene. The tissue specificity has been shown by collaborators to overlap the expression pattern of IGF2 very closely, and control of IGF2 function remains one possible role for the GPC3 gene. More incisive analyses of gene action should be possible in a mouse model, which has been constructed by collaborators who have disrupted the mouse gpc3 gene. The knockout mice show features of overgrowth, and the interactions of gpc3 and other genes, including those in the IGF2 growth regulatory pathway, are being tested in the progeny of appropriate crosses.