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 has been shown by collaborators to overlap the expression pattern of IGF2 very closely, so that GPE3 is likely involved in growth control in a pathway overlapping IGF2 function. In a mouse model, GPC3 has been disrupted by collaborators. The knockout mice show features of overgrowth, and the interactions of gpc3 with genes in the IGF2 growth regulatory pathway, assessed in crosses of mice modified in various genes, indicate that GPC3 acts in a pathway that interacts with but is at least partially independent of IGF2 action. A new autosomal candidate locus for overgrowth control has been identified with collaborators, involving an intracellular signaling pathway that may be downstream in such a pathway. It is presently being characterized.
| Chiao, Eric; Fisher, Peter; Crisponi, Laura et al. (2002) Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling. Dev Biol 243:185-206 |
| Lin, H; Huber, R; Schlessinger, D et al. (1999) Frequent silencing of the GPC3 gene in ovarian cancer cell lines. Cancer Res 59:807-10 |
| Huber, R; Hansen, R S; Strazzullo, M et al. (1999) DNA methylation in transcriptional repression of two differentially expressed X-linked genes, GPC3 and SYBL1. Proc Natl Acad Sci U S A 96:616-21 |
