Glypican 3 Action In Overgrowth Syndromes

一组表型相似的巨人症/过度生长综合征包括一种x连锁形式，Simpson-Golabi-Behmel （SGBS）综合征。尽管许多类似的病症与11p15.5的不同位点相关联，使得这些疾病的病因复杂，但我们发现，SGBS的结果明确是由glypican 3 （GPC3）基因的功能丧失突变引起的。该基因的大部分基因组（超过600kb）几乎都已被测序和分析，对该基因的生理研究也已开始。对启动子的研究表明，它包含初级转录因子位点，这些位点在x失活染色体中被甲基化以关闭它；但在一些类型的细胞中，即使没有甲基化，转录也会失败，因此，在确定基因在组织中的紧密分布时，必须涉及额外的转录因子。组织特异性与IGF2的表达模式非常紧密地重叠，因此GPC3可能在与IGF2功能重叠的途径中参与生长控制。在一个小鼠模型中，与博士实验室的合作。G. Pilia和A. Efstradiatis，我们现在已经破坏了小鼠的gpc3并分析了由此产生的表型。基因敲除小鼠表现出过度生长的特征。gpc3与igf2生长调控通路中基因的相互作用已经在不同基因修饰的小鼠杂交中被评估。结果表明，gpc3在独立于ifg2的途径中起作用，但这两个途径很可能在一个共同点收敛。在一种独立的方法中，我们现在正试图通过研究散发性巨人症中因易位而中断的基因，来寻找可能导致过度生长的其他基因或途径。一个新的控制过度生长的候选区域已经被确定，目前正在进行制图和测序，以确定它是否标志着另一个基因参与了器官和身体大小设定值的总体决定。

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. 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. Studies of the promoter have shown that it contains primary transcription factor sites that are methylated to shut it down in X-inactivated chromosomes; 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 overlaps the expression pattern of IGF2 very closely, so that GPC3 is likely involved in growth control in a pathway overlapping IGF2 function. In a mouse model, in collaboration with the Laboratories of Drs. G. Pilia and A. Efstradiatis, we have now disrupted gpc3 in mice and analyzed the resultant phenotype. The knockout mice show features of overgrowth. The interactions of gpc3 with genes in the igf2 growth regulatory pathway have been assessed in crosses of mice modified in various genes. The results show that gpc3 acts in a pathway independent of ifg2 action, but the two pathways very likely converge at a common point. In an independent approach, we are now attempting to find additional genes or pathways that can give rise to overgrowth, by investigating genes interrupted by translocations in sporadic cases of gigantism. A new candidate region for overgrowth control has been identified, and mapping and sequencing are now ongoing to find out if it marks another gene involved in the overall determination of the set point for organ and body size.