Glypican 3 Action In Overgrowth Syndromes

一组表型相似的肥大症/过度生长综合征包括一种X连锁形式，G-G-Behmel（SGBS）综合征。虽然一些类似的条件映射到11p15.5的各个位点，使这些疾病的病因复杂，我们表明，SGBS的结果明确从磷脂酰肌醇蛋白聚糖3（GPC 3）基因的功能丧失突变。几乎所有非常大的基因组范围（超过600 kb）的基因已经测序和分析，和生理学研究的基因已经开始。对启动子的研究表明，它含有主要的转录因子位点，这些位点在X失活的染色体中被甲基化以关闭它;但在几种类型的细胞中，即使没有甲基化，转录也失败了，因此必须有额外的转录因子参与决定基因的紧密组织分布。组织特异性与IGF 2的表达模式非常接近，因此GPC 3可能在与IGF 2功能重叠的途径中参与生长控制。在小鼠模型中，与G. Pilia和A.事实上，我们现在已经破坏了小鼠中的gpc 3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。gpc 3与igf 2生长调节途径中基因的相互作用已经在不同基因修饰的小鼠杂交中进行了评估。结果表明，gpc 3的作用途径独立于ifg 2的作用，但这两条途径很可能在一个共同点上会聚。在一个独立的方法中，我们现在正试图通过研究在零星的自闭症病例中被易位中断的基因，来寻找其他可能引起过度生长的基因或途径。已经确定了一个新的过度生长控制的候选区域，现在正在进行绘图和测序，以确定它是否标志着另一个参与器官和身体大小设定点的整体决定的基因。

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.