Glypican 3 Action In Overgrowth Syndromes

磷脂酰肌醇蛋白聚糖 3 在过度生长综合征中的作用

• 批准号: 6508426
• 负责人: David Schlessinger
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6508426
• 关键词: cell growth regulation; developmental genetics; gene expression; gene mutation; gene targeting; genetically modified animals; gigantisms; human tissue; insulinlike growth factor; laboratory mouse; nucleic acid sequence; protein structure function; proteoglycan; transcription factor

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.

一组表型相似的巨大主义/过度生长综合症包括一种X连锁形式，Simpson-Golabi-Behmel（SGBS）综合征。尽管许多类似的条件在11p15.5中映射到各种基因座，这使这些疾病复合物的病因学，但我们表明，Glypican 3（GPC3）基因的功能丧失突变无明显地导致SGBS结果。对基因（超过600 kb）的几乎所有非常重要的基因组程度进行了测序和分析，并且对基因的生理研究开始了。对启动子的研究表明，它包含甲基化的主要转录因子位点，以将其关闭在X灭活的染色体中。但是，在几种类型的细胞中，即使没有甲基化，转录也会失败，因此必须在确定基因的紧密组织分布中涉及其他转录因子。组织特异性非常紧密地重叠IGF2的表达模式，因此GPC3可能参与了与IGF2函数重叠的途径中的生长控制。在鼠标模型中，与Drs的实验室合作。 G. pilia和A. eftradiatis，我们现在已经中断了小鼠的GPC3，并分析了所得的表型。淘汰小鼠表现出过度生长的特征。已经在各种基因修饰的小鼠的杂交中评估了GPC3与IGF2生长调节途径中基因的相互作用。结果表明，GPC3在独立于IFG2动作的途径中起作用，但是这两种途径很可能会在公共点收敛。在一种独立的方法中，我们现在正在尝试通过调查零星巨大主义病例中易位的基因中断的基因，从而找到可能导致过度生长的其他基因或途径。已经确定了一个新的用于过度生长控制的候选区域，现在正在进行映射和测序，以找出它是否标志着器官和身体大小的设定点的总体确定涉及的另一个基因。