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.

一组表型相似的巨人症/过度生长综合征包括一种 X 连锁形式，辛普森-戈拉比-贝梅尔 (SGBS) 综合征。尽管许多类似的情况映射到 11p15.5 中的各个位点，使得这些疾病的病因学变得复杂，但我们表明 SGBS 明确是由磷脂酰肌醇蛋白聚糖 3 (GPC3) 基因的功能丧失突变引起的。该基因的几乎所有非常大的基因组范围（超过 600 kb）都已被测序和分析，并且该基因的生理学研究已经开始。对启动子的研究表明，它含有初级转录因子位点，这些位点被甲基化以使其在 X 失活染色体中关闭；但在几种类型的细胞中，即使没有甲基化，转录也会失败，因此必须涉及额外的转录因子来确定基因的紧密组织分布。组织特异性与 IGF2 的表达模式非常密切地重叠，因此 GPC3 可能在与 IGF2 功能重叠的途径中参与生长控制。在小鼠模型中，与博士实验室合作。 G. Pilia 和 A. Efstradiatis，我们现在已经破坏了小鼠的 gpc3 并分析了所得的表型。基因敲除小鼠表现出过度生长的特征。 gpc3 与 igf2 生长调节途径中基因的相互作用已在经过各种基因修饰的小鼠杂交中进行了评估。结果表明，gpc3 在独立于 ifg2 作用的途径中发挥作用，但这两条途径很可能会聚在一个共同点。我们现在正以独立的方法，通过研究散发的巨人症病例中因易位而中断的基因，试图找到可能导致过度生长的额外基因或途径。一个用于过度生长控制的新候选区域已经被发现，目前正在进行绘图和测序，以查明它是否标记了另一个参与器官和身体大小设定点总体确定的基因。