Simpson-Golabi-Behmel Syndrome (or SGBS) is a gigantism/overgrowth syndrome that predisposes affected individuals -- presumably as a consequence of tissue hypertrophy -- to the development of certain embryonal tumors. This proposal is based on the finding that lesions in a particular glycoprotein, glypican 3 (GPC3), cause the syndrome. This is the first proteoglycan in which lesions are shown to result in genetic disease. The investigators have shown that GPC3 is highly expressed in the same embryonic tissues that tend to overgrow in its absence in SGBS patients, and have obtained evidence that it interacts with insulin-like growth factor 2 (IGF2). The working hypothesis is that in tissues where, and at the times when, GPC3 is expressed, an interaction of GPC3 with IGF2 influences the rate of growth.
They aim to analyze further the structure of the GPC3 gene and protein, and their involvement in growth control. The proposed work uses a combination of biochemical studies of the protein and its interaction with IGF2, and genetic tests that include disruption of the GPC3 gene and provision of an extra transgenic copy in mice. The work should also provide diagnostic tests for the discrimination of SGBS for the phenotypically similar Beckwith-Weidemann Syndrome, should aid in the analysis of the nature of tissue hypertrophy and overgrowth syndromes, and can provide information about whether GPC3 is a suppressor of some tumors and a possible marker for others.
| Huber, R; Schlessinger, D; Pilia, G (1998) Multiple Sp1 sites efficiently drive transcription of the TATA-less promoter of the human glypican 3 (GPC3) gene. Gene 214:35-44 |
| Huber, R; Crisponi, L; Mazzarella, R et al. (1997) Analysis of exon/intron structure and 400 kb of genomic sequence surrounding the 5'-promoter and 3'-terminal ends of the human glypican 3 (GPC3) gene. Genomics 45:48-58 |
