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。虽然一些相似的情况映射到11p15.5的不同位点，使得这些疾病的病因复杂，但我们明确地表明，SGBs是由Glypical3(GPC3)基因的功能丧失突变造成的。几乎所有非常大的基因组范围(超过600kb)都已被测序和分析，并开始了对该基因的生理学研究。对启动子的研究表明，它包含初级转录因子位点，在X-失活的染色体中，甲基化使其关闭；但在几种类型的细胞中，即使没有甲基化，转录也无法进行，因此必须有额外的转录因子参与确定基因的紧密组织分布。组织特异性与IGF2的表达模式非常相似，因此GPC3可能通过与IGF2功能重叠的途径参与生长控制。在小鼠模型中，我们与G.Pilia博士和A.Efstradiatis博士的实验室合作，现在已经扰乱了小鼠的GPC3并分析了结果的表型。基因敲除的小鼠表现出过度生长的特征。GPC3与IGF2生长调控途径中的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，GPC3在一条独立于ifg2作用的途径中起作用，但这两条途径很可能汇聚在一个公共点。在一种独立的方法中，我们现在正试图通过调查零星的巨人症病例中被易位打断的基因，来寻找可能导致过度生长的额外基因或途径。一个新的控制过度生长的候选区域已经被识别出来，目前正在进行绘图和测序，以找出它是否标志着另一个基因，该基因参与了器官和身体大小设定点的总体决定。

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.