Glypican 3 Action in Overgrowth Syndromes

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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. In the last year, 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. The genomic DNA proved to have a second glypican (GPC4) as the next centromeric gene, and the sequence and tissue distribution of that gene have been compared; in two patients, deletions in GPC3 extend into GPC4, but the patients are clearly viable, and there is no clear additional phenotype conferred by the larger deletions. Studies of the promoter have shown that it contains primary transcription factor sites that are methylated to shut it down in X-inactivated chromosomes, and that methylation is sufficient to shut off transcription; 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 has been shown by collaborators to overlap the expression pattern of IGF2 very closely, and control of IGF2 function remains one possible role for the GPC3 gene. More incisive analyses of gene action should be possible in a mouse model, which has been constructed by collaborators who have disrupted the mouse gpc3 gene. The knockout mice show features of overgrowth, and the interactions of gpc3 and other genes, including those in the IGF2 growth regulatory pathway, are being tested in the progeny of appropriate crosses.